Macrophage activation syndrome (MAS), in its secondary form, often complicates rheumatic diseases but rarely constitutes a mode of revelation. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unk...Macrophage activation syndrome (MAS), in its secondary form, often complicates rheumatic diseases but rarely constitutes a mode of revelation. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology that primarily affects women in adulthood. MAS is a serious condition that may be the first presentation of SLE. Here, we report the case of a 4-year-old female with MAS as the primary manifestation of Systemic Lupus Erythematosus (SLE). In this case, we outline the characteristics of a complex case of SLE that was initially accompanied with MAS, and also review the literature to discuss the clinical, biological, and therapeutic aspects of this condition.展开更多
Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its ...Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.展开更多
Macrophage activation syndrome (MAS) is linked to inappropriate stimulation of macrophage cells in the bone marrow and lymphoid system, resulting in abnormal phagocytosis of figurative blood elements and the release o...Macrophage activation syndrome (MAS) is linked to inappropriate stimulation of macrophage cells in the bone marrow and lymphoid system, resulting in abnormal phagocytosis of figurative blood elements and the release of pro-inflammatory cytokines. It is a rare and serious hyper-inflammatory condition of diagnostic and therapeutic emergency. MAS is characterized by non-specific clinical and laboratory signs associated with images of hemophagocytosis. MAS is either “primary” (familial or pediatric forms), or “secondary/reactive” to infection, neoplasia, or autoimmune disease. Hemopathies dominate MAS secondary to neoplasia. B-type acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the proliferation and accumulation of B lymphoid progenitors, blocked at an early stage of differentiation, leading to suppression of polyclonal hematopoiesis and subsequent development of signs associated with bone marrow failure. In this context, we report the observation of a macrophage activation syndrome (MAS) associated with ALL, diagnosed at Hôpital Principal de Dakar/Senegal, in a 69-year-old patient with a well-controlled type 2 diabetes under oral antidiabetic therapy (OAD) and good general condition.展开更多
In a recent article on World J Clin Cases 2019;7:3859-3865,Sun et al reported a case of 36-year-old female with macrophage activity syndrome as an onset of systemic lupus erythematosus.Although this is a very interest...In a recent article on World J Clin Cases 2019;7:3859-3865,Sun et al reported a case of 36-year-old female with macrophage activity syndrome as an onset of systemic lupus erythematosus.Although this is a very interesting case,some concerns still need to be addressed.First,the patient had an extremely elevated serum ferritin but a normal C-reactive protein level,which was unparallel with the inflammatory condition before she received any treatments.Second,the diagnosis of systemic lupus erythematosus seemed to be insufficient according to the patient’s medical information presented,most of which were not specific to lupus but could be explained by macrophage activity syndrome.Hence,more medical information on the patient should be provided,and a profound discussion needs to be addressed.展开更多
BACKGROUND Macrophage activation syndrome(MAS)can be a fatal complication of rheumatic disorders,which occurs most commonly in patients with systemic juvenile idiopathic arthritis or systemic lupus erythematosus.It ha...BACKGROUND Macrophage activation syndrome(MAS)can be a fatal complication of rheumatic disorders,which occurs most commonly in patients with systemic juvenile idiopathic arthritis or systemic lupus erythematosus.It has rarely been reported in patients with dermatomyositis.Here,we describe a fatal case of MAS that developed in an adult patient with dermatomyositis.CASE SUMMARY A 44-year-old woman was admitted to our hospital with fever,generalized rash and muscle weakness.Fifteen days later,the fever persisted after the use of antibiotics,and repeat blood culture was negative.The patient then exhibited a typical Gottron sign and diffuse erythema on the face and neck,which were consistent with a diagnosis of dermatomyositis.The patient exhibited limb muscle strength of 2,and electromyography was suggestive of muscle-derived damage,which also supported a diagnosis of dermatomyositis.In addition,the patient exhibited high serum ferritin level,cytopenia,liver dysfunction,coagulopathy,enlarged spleen and hypertriglyceridemia,all of which are typical manifestations of MAS.The patient was diagnosed with dermatomyositis complicated by MAS.Although a high dose of methylprednisolone was administered for 15 d,the patient’s condition continued to deteriorate and central nervous system symptoms developed.Eventually,treatment was discontinued,and the patient died.CONCLUSION MAS is an important,potentially fatal,complication of dermatomyositis.Although MAS is rare in dermatomyositis,it should be considered in the differential diagnosis of an unexplained change of hemoglobin,platelet,fibrinogen,ferritin and triglyceride,which may complicate dermatomyositis.展开更多
Endothelial progenitor cells secrete a variety of growth factors that inhibit inflammation, promote angiogenesis and exert neuroprotective effects. Therefore, in this study, we investigated whether endothelial progeni...Endothelial progenitor cells secrete a variety of growth factors that inhibit inflammation, promote angiogenesis and exert neuroprotective effects. Therefore, in this study, we investigated whether endothelial progenitor cell-conditioned medium might have therapeutic effectiveness for the treatment of spinal cord injury using both in vitro and in vivo experiments. After primary culture of bone marrow-derived macrophages, lipopolysaccharide stimulation was used to classically activate macrophages to their proinflammatory phenotype. These cells were then treated with endothelial progenitor cell-conditioned medium or control medium. Polymerase chain reaction was used to determine mR NA expression levels of related inflammatory factors. Afterwards, primary cultures of rat spinal cord neuronal cells were prepared and treated with H2O2and either endothelial progenitor cell-conditioned medium or control medium. Hoechst 33258 and propidium iodide staining were used to calculate the proportion of neurons undergoing apoptosis. Aortic ring assay was performed to assess the effect of endothelial progenitor cell-conditioned medium on angiogenesis. Compared with control medium, endothelial progenitor cell-conditioned medium mitigated the macrophage inflammatory response at the spinal cord injury site, suppressed apoptosis, and promoted angiogenesis. Next, we used a rat model of spinal cord injury to examine the effects of the endothelial progenitor cell-conditioned medium in vivo. The rats were randomly administered intraperitoneal injection of PBS, control medium or endothelial progenitor cell-conditioned medium, once a day, for 6 consecutive weeks. Immunohistochemistry was used to observe neuronal morphology. Terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay was performed to detect the proportion of apoptotic neurons in the gray matter. The Basso, Beattie and Bresnahan Locomotor Rating Scale was used to evaluate the recovery of motor function of the bilateral hind limbs after spinal cord injury. Compared with the other two groups, the number of axons was increased, cavities in the spinal cord were decreased, the proportion of apoptotic neurons in the gray matter was reduced, and the Basso, Beattie and Bresnahan score was higher in the endothelial progenitor cell-conditioned medium group. Taken together, the in vivo and in vitro results suggest that endothelial progenitor cell-conditioned medium suppresses inflammation, promotes angiogenesis, provides neuroprotection, and promotes functional recovery after spinal cord injury.展开更多
Idiopathic pulmonary fibrosis(IPF)is a fatal interstitial lung disease with limited therapeutic options.Macrophages,particularly alternatively activated macrophages(M2),have been recognized to contribute to the pathog...Idiopathic pulmonary fibrosis(IPF)is a fatal interstitial lung disease with limited therapeutic options.Macrophages,particularly alternatively activated macrophages(M2),have been recognized to contribute to the pathogenesis of pulmonary fibrosis.Therefore,targeting macrophages might be a viable therapeutic strategy for IPF.Herein,we report a potential nanomedicinebased gene therapy for IPF by modulating macrophage M2 activation.In this study,we illustrated that the levels of pleckstrin homology and FYVE domain containing 1(Plekhf1)were increased in the lungs originating from IPF patients and PF mice.Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation.Mechanistically,Plekhf1 was upregulated by IL-4/IL-13 stimulation,after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis.Therefore,intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis,concomitant with a significant reduction in M2 macrophage accumulation in the lungs.In conclusion,Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis,and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.展开更多
BACKGROUND Adult-onset Still’s disease(AOSD)is a rare systemic inflammatory disease,which is characterized by daily fever and arthritis,with an evanescent rash and neutrophilic leukocytosis.To date,there has been no ...BACKGROUND Adult-onset Still’s disease(AOSD)is a rare systemic inflammatory disease,which is characterized by daily fever and arthritis,with an evanescent rash and neutrophilic leukocytosis.To date,there has been no definite laboratory or imaging test available for diagnosing AOSD;the diagnosis is one of exclusion,which can be very challenging.In particular,AOSD patients may experience different complications affecting their clinical picture,management,and prognosis.The treatment of AOSD remains largely empirical and involves therapeutic agents.CASE SUMMARY We report the case of a 36-year-old woman who presented with fever,red rash,arthralgia,and sore throat.Her serum ferritin level and white blood cell count were markedly elevated,and the first diagnosis 22 years prior was"juvenile rheumatoid arthritis of systemic type".The patient was treated with prednisone,sulfasalazine,methotrexate,and leflunomide.After remission of her symptoms,the patient stopped taking the medications,and the disease recurred.Ultimately,the patient was diagnosed with adult-onset Still's disease.Relapse occurred several times due to self-medication withdrawal,and an interleukin-6 antagonist(tocilizumab/Actemra)was administered to control the disease.Recently,she was hospitalized because an incision did not heal,and the patient suddenly developed high fever and diarrhea during hospitalization.The patient's disease progressed violently and quickly developed into macrophage activation syndrome,disseminated intravascular coagulation,shock,and multiple organ failure.The patient had sudden cardiac arrest,and she died despite emergency rescue efforts.CONCLUSION AOSD patients need regular follow-up in the long-term treatment process,and must press formulary standard medication,and do not voluntarily withdraw or reduce the dose.Otherwise it may cause disease back-and-forth or serious lifethreatening complications.Meanwhile,strict management of trauma,infections,tumors,and other diseases may contribute to improved outcomes in patients with complications.展开更多
Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunctio...Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.展开更多
Objective: To evaluate the effect of short-term and long-term immunization of recombinant disorganized muscle protein-1(r DIM-1) in rodents against human filarial parasite Brugia malayi.Methods: Recombinant Brugia mal...Objective: To evaluate the effect of short-term and long-term immunization of recombinant disorganized muscle protein-1(r DIM-1) in rodents against human filarial parasite Brugia malayi.Methods: Recombinant Brugia malayi DIM-1(rDIM-1 bm) protein was cloned, expressed and purified using a Ni-NTA affinity column. Mastomys coucha were immunized with rDIM-1 bm in three immunization schedules: short-term(3-dose of rDIM-1 bm), and long-term(booster doses till 3-and 6-week) and subsequently challenged with infective third-stage larvae of filarial parasite Brugia malayi(L3). Microfilaraemia was monitored in L3 exposed groups on day 90 post larval inoculation(p.l.i.) and continued till day 205 p.l.i. On day 205 p.l.i. all the infected animals were killed and total worm burden was estimated. Cellular proliferative response, macrophage activity, nitric oxide(NO) release, specific IgG and its subtypes, IgE, IgA and Th1(IFN-γ, TNF-ααand IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release were determined. Results: Of the 3 different immunization schedules, shortterm immunization(3-dose schedule) showed better reduction in microfilarial burden(36%-63%) in the peripheral circulation, adult worm load(52%), whereas long-term immunization(3-and 6-week schedule) exerted less effect on peripheral microfilariae count(9%-58%), and adult worm burden(9%-12.5%). Short-term immunization resulted in upregulation of cellular proliferation, macrophages activity, NO release, specific IgG, IgG1, IgG2 a, Ig G2 b, IgE and IgA levels and both Th1(IFN-γ, TNF-α and IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release whereas long-term immunization(3-and 6-week schedule) exerted less effect on parasite burden and showed mixed immunological responses. None of the rDIM-1 bm administration schedules induced any pathology in lymphoid tissues, or alteration in mast cell number and granularity. Conclusions: The short-term immunization with rDIM-1 bm(3-dose schedule) induces robust immune responses and protects the host from filarial parasite infection.展开更多
The relationship between reactive oxygen and nitrogen species(ROS-RNS)secretion and the concomitant biocorrosion of degradable magnesium(Mg)materials is poorly understood.We found that Mg foils implanted short term in...The relationship between reactive oxygen and nitrogen species(ROS-RNS)secretion and the concomitant biocorrosion of degradable magnesium(Mg)materials is poorly understood.We found that Mg foils implanted short term in vivo(24 h)displayed large amounts of proinflammatory F4/80+/iNOS+macrophages at the interface.We sought to investigate the interplay between biodegrading Mg materials(98.6%Mg,AZ31&AZ61)and macrophages(RAW 264.7)stimulated with lipopolysaccharide(RAW 264.7^(LPS))to induce ROS-RNS secretion.To test how these proinflammatory ROS-RNS secreting cells interact with Mg corrosion in vitro,Mg and AZ61 discs were suspended approximately 2 mm above a monolayer of RAW 264.7 cells,either with or without ^(LPS).The surfaces of both materials showed acute(24 h)changes when incubated in the proinflammatory RAW 264.7^(LPS) environment.Mg discs incubated with RAW 264.7^(LPS) macrophages showed greater corrosion pitting,while AZ61 showed morphological and elemental bulk product changes via scanning electron microscopy-energy dispersive X-ray spectroscopy(SEM-EDX).X-ray photoelectron spectroscopy(XPS)analysis showed a reduction in the Ca/P ratio of the surface products for AZ61 disc incubated with RAW 264.7^(LPS),but not the Mg discs.Moreover,RAW 264.7^(LPS) macrophages were found to be more viable in the acute biodegradative environment generated by Mg materials,as demonstrated by calcein-AM and cleaved(active)caspase-3 staining(CC3).^(LPS) stimulation caused an increase in ROS-RNS,and a decrease in antioxidant peroxidase activity.Mg and AZ61 were found to change this ROS-RNS balance,independently of physiological antioxidant mechanisms.The findings highlight the complexity of the cellular driven acute inflammatory responses to different biodegradable Mg,and how it can potentially affect performance of these materials.展开更多
CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+...CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+ Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4+CD25+ Tregs on recipient mouse resident F4/80+macrophages was investigated using a mouse model in which allogeneic donor CD4+CD25+ Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80+ macrophages in the recipient mice that received the allogeneic CD4+CD25+ Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand I(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4+CD25- T cells (Teffs) or no cells. The resident F4/80+ macrophages of the recipient mice injected with the allogeneic donor CD4+CD25+ Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-IO production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4+CD25+ Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4+CD25+ Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4+CD25+ Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.展开更多
The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation.However,the role of PU.1 in alternatively activated macrophage(AAM)and asthmatic inflammation has yet been investiga...The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation.However,the role of PU.1 in alternatively activated macrophage(AAM)and asthmatic inflammation has yet been investigated.Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation.In response to the challenge of DRA(dust mite,ragweed,and Aspergillus)allergens,conditional PU.1-deficient(PU/ER(T)^(+/-))mice displayed attenuated allergic airway inflammation,including decreased alveolar eosinophil infiltration and reduced production of IgE,which were associated with decreased mucous glands and goblet cell hyperplasia.The reduced asthmatic inflammation in PU/ER(T)^(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type(WT)macrophages.Moreover,after treating PU/ER(T)^(+/-) mice with tamoxifen to rescue PU.1 function,the allergic asthmatic inflammation was significantly restored.In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3(Ym-1)and resistin-like molecule alpha 1(Fizz-1),two specific markers of AAM polarization.In addition,PU.1 expression in macrophages was inducible in response to IL-4 challenge,whichwas associated with phosphorylation of signal transducer and activator of transcription 6(STAT6).Furthermore,DRAchallenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)^(+/-) mice compared with WT mice.These data,all together,indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.展开更多
Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children,with onset before age 16 and lasting for more than 6 weeks.JIA is a highly heterogeneous condition with...Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children,with onset before age 16 and lasting for more than 6 weeks.JIA is a highly heterogeneous condition with various consequences for health and quality of life.For some JIA patients,early detection and intervention remain challenging.As a result,further investigation of the complex and unknown mechanisms underlying JIA is required.Advances in technology now allow us to describe the biological heterogeneity and function of individual cell populations in JIA.Through this review,we hope to provide novel ideas and potential targets for the diagnosis and treatment of JIA by summarizing the current findings of single-cell RNA sequencing studies and understanding how the major cell subsets drive JIA pathogenesis.展开更多
Background Macrophage activation syndrome(MAS)is a major cause of morbidity and mortality in pediatric rheumatology.We aimed to further understand the clinical features,treatment,and outcome of MAS in China.Methods A ...Background Macrophage activation syndrome(MAS)is a major cause of morbidity and mortality in pediatric rheumatology.We aimed to further understand the clinical features,treatment,and outcome of MAS in China.Methods A multi-center cohort study was performed in seven hospitals in China from 2012 to 2018.Eighty patients with MAS were enrolled,including 53 cases with systemic juvenile idiopathic arthritis(SJIA-MAS),10 cases of Kawasaki disease(KD-MAS),and 17 cases of connective tissue disease(CTD-MAS).The clinical and laboratory data were collected before(pre-),at onset,and during full-blown stages of MAS.We compared the data among the SJIA-MAS,KD-MAS,and CTD-MAS subjects.Results 51.2%of patients developed MAS when the underlying disease was first diagnosed.In patients with SJIA,22.6%(12/53)were found to have hypotension before the onset of SJIA-MAS.These patients were also found to have significantly increased aspartate aminotransferase(AST)and lactate dehydrogenase(LDH),as well as decreased albumin(P<0.05),but no difference in alanine aminotransferase,ferdtin,and ratio of ferritin/erythrocyte sedimentation rate(ESR)at onset of MAS when compared to pre-MAS stages of the disease.In addition,ferritin and ratio of ferritin/ESR were significantly elevated in patients at full-blown stages of SJIA-MAS compared to pre-MAS stage.Significantly increased ferritin and ratio of ferritin/ESR were also observed in patients with SJIA compared to in KD and CTD.Receiver-operating characteristic analysis showed that 12,217.5μg/L of ferritin and 267.5 of ferritin/ESR ratio had sensitivity(80.0%and 90.5%)and specificity(88.2%and 86.7%),respectively,for predicting full-blown SJIA-MAS.The majority of the patients received corticosteroids(79/80),while biologic agents were used in 12.5%(10/80)of cases.Tocilizumab was the most commonly selected biologic agent.The overall mortality rate was 7.5%.Conclusions About half of MAS occurred when the underlying autoimmune diseases(SJIA,KD,and CTD)were first diagnosed.Hypotension could be an important manifestation before MAS diagnosis.Decreased albumin and increased AST,LDH,ferritin,and ratio of ferritin/ESR could predict the onset or full blown of MAS in patient with SJIA.展开更多
One major mechanism through which macrophages effectively kill tumor cells requires cell to cell contact, indicating that certain molecules expressed on cell surface of activated macrophages may mediate the tumoricida...One major mechanism through which macrophages effectively kill tumor cells requires cell to cell contact, indicating that certain molecules expressed on cell surface of activated macrophages may mediate the tumoricidal capability. Tumor necrosis factor (TNF) and nitric oxide (NO) are the two classical mediators of tumor cell death. However, evidence of discrepancy is accumulating indicating these known mediators do not appear to account for the broad and potent tumoricidal activity of macrophages. To obtain a full repertoire of tumoricidal activation-associated membrane proteins, we combined one-dimensional SDS-PAGE with capillary liquid chromatographytandem mass spectrometry (LC-MS/MS). Using this technique, we identified 454 activated macrophage specifically expressed proteins with extremely high confidence, including most known activation markers of macrophages, such as NO synthase (iNOS), Ym1, cyclooxygenase, etc. Membrane bound TNF-α was also identified on activated macrophages. However, it was also detected on thioglycolate elicited macrophages, indicating this molecule may not play a key role in conjugation-dependent tumor cell killing. In contrast, although NO has not been assigned as an effector molecule of conjugation-dependent tumoricidal pathway, iNOS was identified from membrane fraction of activated macrophages, suggesting NO may be involved in conjugation-dependent tumoricidal mechanism, because iNOS association with plasma membrane is ideally suited to deliver NO directly into the contacted tumor cells. This research provides not only new insights into macrophage conjugation-dependent tumoricidal mechanisms, but also a valuable data set of macrophage activation associated membrane proteins, thus providing better understanding of the functional mechanisms of macrophages in anti-tumor and other biological processes.展开更多
Background Macrophage activation syndrome(MAS)is a rare,life-threatening complication of Kawasaki disease(KD).Early recognition and treatment of MAS are very important,but sometimes it is difficult to distinguish MAS ...Background Macrophage activation syndrome(MAS)is a rare,life-threatening complication of Kawasaki disease(KD).Early recognition and treatment of MAS are very important,but sometimes it is difficult to distinguish MAS from a severe form of KD.Data sources A PubMed search was performed in Clinical Queries using the key terms“macrophage activation syndrome or secondary hemophagocytic lymphohistiocytosis(HLH)”and“Kawasaki disease”.Results KD patients with MAS show high intravenous immunoglobulin(IVIG)resistance and coronary complications.Mortality is also as high as MAS in other diseases.Persistent fever greater than 10 days is highly associated with development of MAS in KD.Splenomegaly is observed in more than two-thirds of KD patients with MAS.Thrombocytopenia is often the earliest laboratory finding of MAS.Hyperferritinemia is highly specific and sensitive for detecting MAS in KD;so,ferritin levels should be checked if there are unexplained clinical exacerbations in KD patients.Given the under-recognition of MAS in KD,it is prudent to consider resistant KD as occult/subclinical MAS.Many KD patients with MAS have good outcomes on immune modulators.However,if KD patients fulfill the HLH-2004 diagnostic criteria,they may undergo longer and more intensive treatment than needed.Conclusions The possible existence of MAS should be taken into account when a KD patient shows persistent fever,splenomegaly,thrombocytopenia,hyperferritinemia,or IVIG resistance.The under-diagnosis of MAS in patients with KD is an important issue to be addressed.Therapeutically,however,there is a possibility of over-treatment of MAS in patients with KD.展开更多
Photoacoustic imaging has been developed to image the immune study at the macro scale.Macrophages play diverse roles in the acute response to infection and tissue repair.However,macrophages activities in acute inflamm...Photoacoustic imaging has been developed to image the immune study at the macro scale.Macrophages play diverse roles in the acute response to infection and tissue repair.However,macrophages activities in acute inflammation at the microscopic level still remain challenging.In this work,we proposed optical-resolution photoacoustic microscopy to promptly monitor the labeled macrophages activities in normal and inflammatory groups.The result showed that many labeled macrophages emerged around the vessels firstly,then exuded into tissues,and finally disappeared in the inflammatory group injected with labeled macrophages.In summary,our method allows us to exactly image and track the immune cells of inflammatory diseases.展开更多
Modulating the activation state and degree of macrophages still remains as a challenge for the topographical design of Ti-based implants.In this work,micro/nano-structured coatings were prepared on Ti substrates by mi...Modulating the activation state and degree of macrophages still remains as a challenge for the topographical design of Ti-based implants.In this work,micro/nano-structured coatings were prepared on Ti substrates by micro-arc oxidation(MAO)and subsequent hydrothermal(HT)treatment.By varying the HT conditions,plate-like nano-structures with an average length of 80,440 or 780 nm were obtained on MAO-prepared micro-topographical surfaces.Depending on the dimensional features of nano-plates,the specimens were noted as Micro,Micro/Nano-180,Micro/Nano-440 and Micro/Nano-780,respectively.The in vitro results showed that the activation state and degree of macrophages could be effectively modulated by the micro/nano-structured surfaces with various dimensional features.Compared to the Micro surface,the Micro/Nano-180 surface activated both M1 and M2 phenotype in macrophages,while the Micro/Nano-440 and Micro/Nano-780 surfaces polarized macrophages to their M1 phenotype.The activation degree of M1 macrophages followed the trend:Micro<Micro/Nano-180<Micro/Nano-440<Micro/Nano-780.However,the osteogenic potential of the activated macrophages in response to various surfaces were in the order:Micro≈Micro/Nano-780<Micro/Nano-180<Micro/Nano-440.Together,the findings presented in this work indicate that engineering nano-structures with controllable dimensional features is a promising strategy to modulate macrophage activation state and degree.In addition,it is essential to determine the appropriate activation degree of M1 macrophages for enhanced osteogenesis.展开更多
C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic ...C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA(apopDNA)could induce macrophage activation and contribute to the initiation and progression of lupus nephritis.It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation.Herein,CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA(CRP/apopDNA complex).Notably,CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone.Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner.These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.展开更多
文摘Macrophage activation syndrome (MAS), in its secondary form, often complicates rheumatic diseases but rarely constitutes a mode of revelation. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology that primarily affects women in adulthood. MAS is a serious condition that may be the first presentation of SLE. Here, we report the case of a 4-year-old female with MAS as the primary manifestation of Systemic Lupus Erythematosus (SLE). In this case, we outline the characteristics of a complex case of SLE that was initially accompanied with MAS, and also review the literature to discuss the clinical, biological, and therapeutic aspects of this condition.
基金supported by the National Key Research and Development Program of China(2020YFA0708004)the National Natural Science Foundation of China(81822047 and 31971088)+1 种基金the Foundation of State Key Laboratory of Component-based Chinese Medicine(CBCM2020104)Yi Wang was supported by the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202002).
文摘Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.
文摘Macrophage activation syndrome (MAS) is linked to inappropriate stimulation of macrophage cells in the bone marrow and lymphoid system, resulting in abnormal phagocytosis of figurative blood elements and the release of pro-inflammatory cytokines. It is a rare and serious hyper-inflammatory condition of diagnostic and therapeutic emergency. MAS is characterized by non-specific clinical and laboratory signs associated with images of hemophagocytosis. MAS is either “primary” (familial or pediatric forms), or “secondary/reactive” to infection, neoplasia, or autoimmune disease. Hemopathies dominate MAS secondary to neoplasia. B-type acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the proliferation and accumulation of B lymphoid progenitors, blocked at an early stage of differentiation, leading to suppression of polyclonal hematopoiesis and subsequent development of signs associated with bone marrow failure. In this context, we report the observation of a macrophage activation syndrome (MAS) associated with ALL, diagnosed at Hôpital Principal de Dakar/Senegal, in a 69-year-old patient with a well-controlled type 2 diabetes under oral antidiabetic therapy (OAD) and good general condition.
文摘In a recent article on World J Clin Cases 2019;7:3859-3865,Sun et al reported a case of 36-year-old female with macrophage activity syndrome as an onset of systemic lupus erythematosus.Although this is a very interesting case,some concerns still need to be addressed.First,the patient had an extremely elevated serum ferritin but a normal C-reactive protein level,which was unparallel with the inflammatory condition before she received any treatments.Second,the diagnosis of systemic lupus erythematosus seemed to be insufficient according to the patient’s medical information presented,most of which were not specific to lupus but could be explained by macrophage activity syndrome.Hence,more medical information on the patient should be provided,and a profound discussion needs to be addressed.
文摘BACKGROUND Macrophage activation syndrome(MAS)can be a fatal complication of rheumatic disorders,which occurs most commonly in patients with systemic juvenile idiopathic arthritis or systemic lupus erythematosus.It has rarely been reported in patients with dermatomyositis.Here,we describe a fatal case of MAS that developed in an adult patient with dermatomyositis.CASE SUMMARY A 44-year-old woman was admitted to our hospital with fever,generalized rash and muscle weakness.Fifteen days later,the fever persisted after the use of antibiotics,and repeat blood culture was negative.The patient then exhibited a typical Gottron sign and diffuse erythema on the face and neck,which were consistent with a diagnosis of dermatomyositis.The patient exhibited limb muscle strength of 2,and electromyography was suggestive of muscle-derived damage,which also supported a diagnosis of dermatomyositis.In addition,the patient exhibited high serum ferritin level,cytopenia,liver dysfunction,coagulopathy,enlarged spleen and hypertriglyceridemia,all of which are typical manifestations of MAS.The patient was diagnosed with dermatomyositis complicated by MAS.Although a high dose of methylprednisolone was administered for 15 d,the patient’s condition continued to deteriorate and central nervous system symptoms developed.Eventually,treatment was discontinued,and the patient died.CONCLUSION MAS is an important,potentially fatal,complication of dermatomyositis.Although MAS is rare in dermatomyositis,it should be considered in the differential diagnosis of an unexplained change of hemoglobin,platelet,fibrinogen,ferritin and triglyceride,which may complicate dermatomyositis.
基金supported by the National Natural Science Foundation of China,No.81171173 and 81672161
文摘Endothelial progenitor cells secrete a variety of growth factors that inhibit inflammation, promote angiogenesis and exert neuroprotective effects. Therefore, in this study, we investigated whether endothelial progenitor cell-conditioned medium might have therapeutic effectiveness for the treatment of spinal cord injury using both in vitro and in vivo experiments. After primary culture of bone marrow-derived macrophages, lipopolysaccharide stimulation was used to classically activate macrophages to their proinflammatory phenotype. These cells were then treated with endothelial progenitor cell-conditioned medium or control medium. Polymerase chain reaction was used to determine mR NA expression levels of related inflammatory factors. Afterwards, primary cultures of rat spinal cord neuronal cells were prepared and treated with H2O2and either endothelial progenitor cell-conditioned medium or control medium. Hoechst 33258 and propidium iodide staining were used to calculate the proportion of neurons undergoing apoptosis. Aortic ring assay was performed to assess the effect of endothelial progenitor cell-conditioned medium on angiogenesis. Compared with control medium, endothelial progenitor cell-conditioned medium mitigated the macrophage inflammatory response at the spinal cord injury site, suppressed apoptosis, and promoted angiogenesis. Next, we used a rat model of spinal cord injury to examine the effects of the endothelial progenitor cell-conditioned medium in vivo. The rats were randomly administered intraperitoneal injection of PBS, control medium or endothelial progenitor cell-conditioned medium, once a day, for 6 consecutive weeks. Immunohistochemistry was used to observe neuronal morphology. Terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay was performed to detect the proportion of apoptotic neurons in the gray matter. The Basso, Beattie and Bresnahan Locomotor Rating Scale was used to evaluate the recovery of motor function of the bilateral hind limbs after spinal cord injury. Compared with the other two groups, the number of axons was increased, cavities in the spinal cord were decreased, the proportion of apoptotic neurons in the gray matter was reduced, and the Basso, Beattie and Bresnahan score was higher in the endothelial progenitor cell-conditioned medium group. Taken together, the in vivo and in vitro results suggest that endothelial progenitor cell-conditioned medium suppresses inflammation, promotes angiogenesis, provides neuroprotection, and promotes functional recovery after spinal cord injury.
基金supported by the National Natural Science Foundation of China(82090015)the China Postdoctoral Science Foundation(2021T140459,2020M681325).
文摘Idiopathic pulmonary fibrosis(IPF)is a fatal interstitial lung disease with limited therapeutic options.Macrophages,particularly alternatively activated macrophages(M2),have been recognized to contribute to the pathogenesis of pulmonary fibrosis.Therefore,targeting macrophages might be a viable therapeutic strategy for IPF.Herein,we report a potential nanomedicinebased gene therapy for IPF by modulating macrophage M2 activation.In this study,we illustrated that the levels of pleckstrin homology and FYVE domain containing 1(Plekhf1)were increased in the lungs originating from IPF patients and PF mice.Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation.Mechanistically,Plekhf1 was upregulated by IL-4/IL-13 stimulation,after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis.Therefore,intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis,concomitant with a significant reduction in M2 macrophage accumulation in the lungs.In conclusion,Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis,and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.
文摘BACKGROUND Adult-onset Still’s disease(AOSD)is a rare systemic inflammatory disease,which is characterized by daily fever and arthritis,with an evanescent rash and neutrophilic leukocytosis.To date,there has been no definite laboratory or imaging test available for diagnosing AOSD;the diagnosis is one of exclusion,which can be very challenging.In particular,AOSD patients may experience different complications affecting their clinical picture,management,and prognosis.The treatment of AOSD remains largely empirical and involves therapeutic agents.CASE SUMMARY We report the case of a 36-year-old woman who presented with fever,red rash,arthralgia,and sore throat.Her serum ferritin level and white blood cell count were markedly elevated,and the first diagnosis 22 years prior was"juvenile rheumatoid arthritis of systemic type".The patient was treated with prednisone,sulfasalazine,methotrexate,and leflunomide.After remission of her symptoms,the patient stopped taking the medications,and the disease recurred.Ultimately,the patient was diagnosed with adult-onset Still's disease.Relapse occurred several times due to self-medication withdrawal,and an interleukin-6 antagonist(tocilizumab/Actemra)was administered to control the disease.Recently,she was hospitalized because an incision did not heal,and the patient suddenly developed high fever and diarrhea during hospitalization.The patient's disease progressed violently and quickly developed into macrophage activation syndrome,disseminated intravascular coagulation,shock,and multiple organ failure.The patient had sudden cardiac arrest,and she died despite emergency rescue efforts.CONCLUSION AOSD patients need regular follow-up in the long-term treatment process,and must press formulary standard medication,and do not voluntarily withdraw or reduce the dose.Otherwise it may cause disease back-and-forth or serious lifethreatening complications.Meanwhile,strict management of trauma,infections,tumors,and other diseases may contribute to improved outcomes in patients with complications.
基金National Natural Science Foundation of China(82070228,81773283)National Key R&D Program of China(No.2019YFC1316204)。
文摘Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.
基金supported by Indian council of Medical Research,New Delhi,India(ICMR approval no.F/802/2010-ECD-11)CSIR,New Delhi,India,for award of Emeritus Scientist(scheme No.21(0963)/13/EMRII grant,29-10-2014)to P.K.M.
文摘Objective: To evaluate the effect of short-term and long-term immunization of recombinant disorganized muscle protein-1(r DIM-1) in rodents against human filarial parasite Brugia malayi.Methods: Recombinant Brugia malayi DIM-1(rDIM-1 bm) protein was cloned, expressed and purified using a Ni-NTA affinity column. Mastomys coucha were immunized with rDIM-1 bm in three immunization schedules: short-term(3-dose of rDIM-1 bm), and long-term(booster doses till 3-and 6-week) and subsequently challenged with infective third-stage larvae of filarial parasite Brugia malayi(L3). Microfilaraemia was monitored in L3 exposed groups on day 90 post larval inoculation(p.l.i.) and continued till day 205 p.l.i. On day 205 p.l.i. all the infected animals were killed and total worm burden was estimated. Cellular proliferative response, macrophage activity, nitric oxide(NO) release, specific IgG and its subtypes, IgE, IgA and Th1(IFN-γ, TNF-ααand IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release were determined. Results: Of the 3 different immunization schedules, shortterm immunization(3-dose schedule) showed better reduction in microfilarial burden(36%-63%) in the peripheral circulation, adult worm load(52%), whereas long-term immunization(3-and 6-week schedule) exerted less effect on peripheral microfilariae count(9%-58%), and adult worm burden(9%-12.5%). Short-term immunization resulted in upregulation of cellular proliferation, macrophages activity, NO release, specific IgG, IgG1, IgG2 a, Ig G2 b, IgE and IgA levels and both Th1(IFN-γ, TNF-α and IL-2) and Th2(IL-4, IL-5, IL-6, IL-10 and IL-13) cytokine release whereas long-term immunization(3-and 6-week schedule) exerted less effect on parasite burden and showed mixed immunological responses. None of the rDIM-1 bm administration schedules induced any pathology in lymphoid tissues, or alteration in mast cell number and granularity. Conclusions: The short-term immunization with rDIM-1 bm(3-dose schedule) induces robust immune responses and protects the host from filarial parasite infection.
基金This work was partially funded by Michigan Tech Research Excellence Fund,National Institutes of Health[grant number R15GM135875(B.P.L.)]the National Science Foundation[grant number DMR 2001076(B.P.L.)],ZA was partially funded by Michigan Tech Undergraduate Research Internship Program.
文摘The relationship between reactive oxygen and nitrogen species(ROS-RNS)secretion and the concomitant biocorrosion of degradable magnesium(Mg)materials is poorly understood.We found that Mg foils implanted short term in vivo(24 h)displayed large amounts of proinflammatory F4/80+/iNOS+macrophages at the interface.We sought to investigate the interplay between biodegrading Mg materials(98.6%Mg,AZ31&AZ61)and macrophages(RAW 264.7)stimulated with lipopolysaccharide(RAW 264.7^(LPS))to induce ROS-RNS secretion.To test how these proinflammatory ROS-RNS secreting cells interact with Mg corrosion in vitro,Mg and AZ61 discs were suspended approximately 2 mm above a monolayer of RAW 264.7 cells,either with or without ^(LPS).The surfaces of both materials showed acute(24 h)changes when incubated in the proinflammatory RAW 264.7^(LPS) environment.Mg discs incubated with RAW 264.7^(LPS) macrophages showed greater corrosion pitting,while AZ61 showed morphological and elemental bulk product changes via scanning electron microscopy-energy dispersive X-ray spectroscopy(SEM-EDX).X-ray photoelectron spectroscopy(XPS)analysis showed a reduction in the Ca/P ratio of the surface products for AZ61 disc incubated with RAW 264.7^(LPS),but not the Mg discs.Moreover,RAW 264.7^(LPS) macrophages were found to be more viable in the acute biodegradative environment generated by Mg materials,as demonstrated by calcein-AM and cleaved(active)caspase-3 staining(CC3).^(LPS) stimulation caused an increase in ROS-RNS,and a decrease in antioxidant peroxidase activity.Mg and AZ61 were found to change this ROS-RNS balance,independently of physiological antioxidant mechanisms.The findings highlight the complexity of the cellular driven acute inflammatory responses to different biodegradable Mg,and how it can potentially affect performance of these materials.
基金The authors wish to thank Drs Shuping Zhou and Zeqing Niu for their kind review of the manuscript, Ms ling Wang, Mr Yabing Liu and Ms Xiaoqiu Liu for their expert technical assistance, Ms Qinghuan Li and ]ianxia Peng for their excellent laboratory management and Mr Baisheng Ren for his outstanding animal husbandry. This work was supported by grants from the National Natural Science Foundation (C81072396, U0832003, YZ C31171407 and 81273201, GL), the Ministry of Science and Technology of China (2010CB945301, YZ) and the Chinese Academy of Sciences for Distinguished Young Scientists (KSCX2-EW-Q-7, GL).
文摘CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4+CD25+ Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4+CD25+ Tregs on recipient mouse resident F4/80+macrophages was investigated using a mouse model in which allogeneic donor CD4+CD25+ Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80+ macrophages in the recipient mice that received the allogeneic CD4+CD25+ Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand I(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4+CD25- T cells (Teffs) or no cells. The resident F4/80+ macrophages of the recipient mice injected with the allogeneic donor CD4+CD25+ Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-IO production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4+CD25+ Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4+CD25+ Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4+CD25+ Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.
基金supported by NIH R01 HL075557,HL068610,and T32 HL082547 and the Department of Veterans Affairs Merit Review Grant 5I01BX000108supported by the grant from National Natural Science Foundation of China(81373424)the Specialized Research Fund for the Doctoral Program of Higher Education of China(20130073120108).
文摘The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation.However,the role of PU.1 in alternatively activated macrophage(AAM)and asthmatic inflammation has yet been investigated.Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation.In response to the challenge of DRA(dust mite,ragweed,and Aspergillus)allergens,conditional PU.1-deficient(PU/ER(T)^(+/-))mice displayed attenuated allergic airway inflammation,including decreased alveolar eosinophil infiltration and reduced production of IgE,which were associated with decreased mucous glands and goblet cell hyperplasia.The reduced asthmatic inflammation in PU/ER(T)^(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type(WT)macrophages.Moreover,after treating PU/ER(T)^(+/-) mice with tamoxifen to rescue PU.1 function,the allergic asthmatic inflammation was significantly restored.In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3(Ym-1)and resistin-like molecule alpha 1(Fizz-1),two specific markers of AAM polarization.In addition,PU.1 expression in macrophages was inducible in response to IL-4 challenge,whichwas associated with phosphorylation of signal transducer and activator of transcription 6(STAT6).Furthermore,DRAchallenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)^(+/-) mice compared with WT mice.These data,all together,indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.
基金supported by grants from the National Key R&D Program of China(No.2021YFC2702003).
文摘Juvenile idiopathic arthritis (JIA) is one of the most common chronic inflammatory rheumatic diseases in children,with onset before age 16 and lasting for more than 6 weeks.JIA is a highly heterogeneous condition with various consequences for health and quality of life.For some JIA patients,early detection and intervention remain challenging.As a result,further investigation of the complex and unknown mechanisms underlying JIA is required.Advances in technology now allow us to describe the biological heterogeneity and function of individual cell populations in JIA.Through this review,we hope to provide novel ideas and potential targets for the diagnosis and treatment of JIA by summarizing the current findings of single-cell RNA sequencing studies and understanding how the major cell subsets drive JIA pathogenesis.
基金This study is funded by Zhejiang Basic Public Welfare Research Project(LGF19H100002).
文摘Background Macrophage activation syndrome(MAS)is a major cause of morbidity and mortality in pediatric rheumatology.We aimed to further understand the clinical features,treatment,and outcome of MAS in China.Methods A multi-center cohort study was performed in seven hospitals in China from 2012 to 2018.Eighty patients with MAS were enrolled,including 53 cases with systemic juvenile idiopathic arthritis(SJIA-MAS),10 cases of Kawasaki disease(KD-MAS),and 17 cases of connective tissue disease(CTD-MAS).The clinical and laboratory data were collected before(pre-),at onset,and during full-blown stages of MAS.We compared the data among the SJIA-MAS,KD-MAS,and CTD-MAS subjects.Results 51.2%of patients developed MAS when the underlying disease was first diagnosed.In patients with SJIA,22.6%(12/53)were found to have hypotension before the onset of SJIA-MAS.These patients were also found to have significantly increased aspartate aminotransferase(AST)and lactate dehydrogenase(LDH),as well as decreased albumin(P<0.05),but no difference in alanine aminotransferase,ferdtin,and ratio of ferritin/erythrocyte sedimentation rate(ESR)at onset of MAS when compared to pre-MAS stages of the disease.In addition,ferritin and ratio of ferritin/ESR were significantly elevated in patients at full-blown stages of SJIA-MAS compared to pre-MAS stage.Significantly increased ferritin and ratio of ferritin/ESR were also observed in patients with SJIA compared to in KD and CTD.Receiver-operating characteristic analysis showed that 12,217.5μg/L of ferritin and 267.5 of ferritin/ESR ratio had sensitivity(80.0%and 90.5%)and specificity(88.2%and 86.7%),respectively,for predicting full-blown SJIA-MAS.The majority of the patients received corticosteroids(79/80),while biologic agents were used in 12.5%(10/80)of cases.Tocilizumab was the most commonly selected biologic agent.The overall mortality rate was 7.5%.Conclusions About half of MAS occurred when the underlying autoimmune diseases(SJIA,KD,and CTD)were first diagnosed.Hypotension could be an important manifestation before MAS diagnosis.Decreased albumin and increased AST,LDH,ferritin,and ratio of ferritin/ESR could predict the onset or full blown of MAS in patient with SJIA.
文摘One major mechanism through which macrophages effectively kill tumor cells requires cell to cell contact, indicating that certain molecules expressed on cell surface of activated macrophages may mediate the tumoricidal capability. Tumor necrosis factor (TNF) and nitric oxide (NO) are the two classical mediators of tumor cell death. However, evidence of discrepancy is accumulating indicating these known mediators do not appear to account for the broad and potent tumoricidal activity of macrophages. To obtain a full repertoire of tumoricidal activation-associated membrane proteins, we combined one-dimensional SDS-PAGE with capillary liquid chromatographytandem mass spectrometry (LC-MS/MS). Using this technique, we identified 454 activated macrophage specifically expressed proteins with extremely high confidence, including most known activation markers of macrophages, such as NO synthase (iNOS), Ym1, cyclooxygenase, etc. Membrane bound TNF-α was also identified on activated macrophages. However, it was also detected on thioglycolate elicited macrophages, indicating this molecule may not play a key role in conjugation-dependent tumor cell killing. In contrast, although NO has not been assigned as an effector molecule of conjugation-dependent tumoricidal pathway, iNOS was identified from membrane fraction of activated macrophages, suggesting NO may be involved in conjugation-dependent tumoricidal mechanism, because iNOS association with plasma membrane is ideally suited to deliver NO directly into the contacted tumor cells. This research provides not only new insights into macrophage conjugation-dependent tumoricidal mechanisms, but also a valuable data set of macrophage activation associated membrane proteins, thus providing better understanding of the functional mechanisms of macrophages in anti-tumor and other biological processes.
文摘Background Macrophage activation syndrome(MAS)is a rare,life-threatening complication of Kawasaki disease(KD).Early recognition and treatment of MAS are very important,but sometimes it is difficult to distinguish MAS from a severe form of KD.Data sources A PubMed search was performed in Clinical Queries using the key terms“macrophage activation syndrome or secondary hemophagocytic lymphohistiocytosis(HLH)”and“Kawasaki disease”.Results KD patients with MAS show high intravenous immunoglobulin(IVIG)resistance and coronary complications.Mortality is also as high as MAS in other diseases.Persistent fever greater than 10 days is highly associated with development of MAS in KD.Splenomegaly is observed in more than two-thirds of KD patients with MAS.Thrombocytopenia is often the earliest laboratory finding of MAS.Hyperferritinemia is highly specific and sensitive for detecting MAS in KD;so,ferritin levels should be checked if there are unexplained clinical exacerbations in KD patients.Given the under-recognition of MAS in KD,it is prudent to consider resistant KD as occult/subclinical MAS.Many KD patients with MAS have good outcomes on immune modulators.However,if KD patients fulfill the HLH-2004 diagnostic criteria,they may undergo longer and more intensive treatment than needed.Conclusions The possible existence of MAS should be taken into account when a KD patient shows persistent fever,splenomegaly,thrombocytopenia,hyperferritinemia,or IVIG resistance.The under-diagnosis of MAS in patients with KD is an important issue to be addressed.Therapeutically,however,there is a possibility of over-treatment of MAS in patients with KD.
基金the National Natural Science Foundation of China (Nos. 91859113 and 81922034)Science Fund for Distinguished Young Scholars of Fujian Province (No. 2018J06024)Science and Technology Program of Jiangxi Province (No. 20171ACB20027)
文摘Photoacoustic imaging has been developed to image the immune study at the macro scale.Macrophages play diverse roles in the acute response to infection and tissue repair.However,macrophages activities in acute inflammation at the microscopic level still remain challenging.In this work,we proposed optical-resolution photoacoustic microscopy to promptly monitor the labeled macrophages activities in normal and inflammatory groups.The result showed that many labeled macrophages emerged around the vessels firstly,then exuded into tissues,and finally disappeared in the inflammatory group injected with labeled macrophages.In summary,our method allows us to exactly image and track the immune cells of inflammatory diseases.
基金supported by the National Natural Science Foundation of China(Grant No.51771233,52071346 and 51604104)China Postdoctoral Science Foundation(Grant No.2018M633164)+1 种基金Innovation-oriented Advanced Technology and Industrial Technology Program Project of Hunan Province(Grant No.2020SK2017)Guangdong Basic and Applied Basic Research Foundation(Grant No.2019A1515110736)。
文摘Modulating the activation state and degree of macrophages still remains as a challenge for the topographical design of Ti-based implants.In this work,micro/nano-structured coatings were prepared on Ti substrates by micro-arc oxidation(MAO)and subsequent hydrothermal(HT)treatment.By varying the HT conditions,plate-like nano-structures with an average length of 80,440 or 780 nm were obtained on MAO-prepared micro-topographical surfaces.Depending on the dimensional features of nano-plates,the specimens were noted as Micro,Micro/Nano-180,Micro/Nano-440 and Micro/Nano-780,respectively.The in vitro results showed that the activation state and degree of macrophages could be effectively modulated by the micro/nano-structured surfaces with various dimensional features.Compared to the Micro surface,the Micro/Nano-180 surface activated both M1 and M2 phenotype in macrophages,while the Micro/Nano-440 and Micro/Nano-780 surfaces polarized macrophages to their M1 phenotype.The activation degree of M1 macrophages followed the trend:Micro<Micro/Nano-180<Micro/Nano-440<Micro/Nano-780.However,the osteogenic potential of the activated macrophages in response to various surfaces were in the order:Micro≈Micro/Nano-780<Micro/Nano-180<Micro/Nano-440.Together,the findings presented in this work indicate that engineering nano-structures with controllable dimensional features is a promising strategy to modulate macrophage activation state and degree.In addition,it is essential to determine the appropriate activation degree of M1 macrophages for enhanced osteogenesis.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.30890141,31100629,and 30671952)Shanghai STC grant(No.10JC1401400)+4 种基金The Program for Outstanding Medical Academic Leaders of Shanghai(Grant No.LJ06011)Jiangsu“Pan-Deng”Project(Grant No.BK2010004)Postdoctoral Science Foundation Funded Project of China(Grant No.20100480538)Shanghai(Grant No.11R21411000)The Research Fellow Fund and Startup Fund for Young Backbone Scholars of Shanghai Medical College,Fudan University.
文摘C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA(apopDNA)could induce macrophage activation and contribute to the initiation and progression of lupus nephritis.It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation.Herein,CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA(CRP/apopDNA complex).Notably,CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone.Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner.These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.