High Mobility Group Box 1 and Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. We identify High Mobility Group Box 1 (HMGB1) as a novel causative factor in the development of cerebral oedema, mediating coagulation, preventing secondary brain damage as well as serving as a novel therapeutic target to limit secondary neurological injury after TBI. As a prototypical danger associated molecular patterns (DAMP), HMGB1 is released from necrotic neurons via a NR2B-mediated mechanism during TBI. The secretion of HMGB1 requires severe injury and tissue hypoperfusion, and is associated with posttraumatic coagulation abnormalities, activation of complement and severe systemic inflammatory response. HMGB1 is clinically associated with elevated intracranial pressure (ICP) in patients and functionally promoted cerebral edema after TBI. The detrimental effects of HMGB1 is mediated at least in part between activation of microglial toll-like receptor 4 (TLR4) and the subsequent expression of the astrocytic water channel aquaporin-4 (AQP4). Anti-HMGB1mAb remarkably inhibited fluid percussion-induced brain edema by inhibiting HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression and improvement of motor function. Our review demonstrates the pathological role of HMGB1 as well as the possible therapeutic valve of HMGB1 in patients with TBI.

Renewal of embryonic and neonatal-derived cardiac-resident macrophages in response to environmental cues abrogated their potential to promote cardiomyocyte proliferation via Jagged-1-Notch1

Cardiac-resident macrophages(CRMs)play important roles in homeostasis,cardiac function,and remodeling.Although CRMs play critical roles in cardiac regeneration of neonatal mice,their roles are yet to be fully elucidated.Therefore,this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration.During mouse cardiac ontogeny,four CRM subsets exist successively:CX3CR1+CCR2-Ly6C-MHCII-(MP1),CX3CR1lowCCR2lowLy6C-MHCII-(MP2),CX3CR1-CCR2+Ly6C+MHCII-(MP3),and CX3CR1+CCR2-Ly6C-MHCII+(MP4).MP1 cluster has different derivations(yolk sac,fetal liver,and bone marrow)and multiple functions population.Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1-Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction.MP2/3 subsets could survive throughout adulthood.MP4,the main population in adult mouse hearts,contributed to inflammation.During ontogeny,MP1 can convert into MP4 triggered by changes in the cellular redox state.These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation.Our findings also shed light on cardiac repair following injury.

Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren’s syndrome by modulating the function of myeloid-derived suppressor cells

Sjögren’s syndrome(SS)is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands.Our previous studies showed that myeloid-derived suppressor cells(MDSCs)exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren’s syndrome(ESS),but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS.In this study,we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes(OE-MSC-Exos)significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels.Moreover,treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice.Mechanistically,OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs.In addition,the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling,indicating an autocrine pathway of MDSC functional modulation by IL-6.Taken together,our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs,possibly constituting a new strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.

TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy

Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival,proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment.A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer treatments.Toll-like receptors(TLRs)have recently been recognized as critical factors involved in tumor pathogenesis,regulating both tumor cells and tumor-infiltrating innate and adaptive immune cells.However,little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism,although there is abundant expression of TLRs in these cells.In this review,we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor microenvironment.In particular,we discuss how malignant tumors regulate metabolism to support their growth and survival,summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells,and further explore potential strategies targeting cell metabolism for TLR-based cancer therapy.An improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.

M1 muscarinic acetylcholine receptor in Alzheimer's disease

The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransmission and five mAChR subtypes （M1-M5） have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists forAD treatment.

Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis

Recent studies have identified olfactory ecto-mesenchymal stem cells （OE-MSCs） as a new type of resident stem cell in the olfactory lamina propria. However, it remains unclear whether OE-MSCs possess any immunoregulatory functions. In this study, we found that mouse OE-MSCs expressed higher transforming growth factor-beta and interleukin-10 levels than bone marrow-derived MSCs. In culture, OE-MSCs exerted their immunosuppressive capacity via directly suppressing effector T-cell proliferation and increasing regulatory T （Treg） cell expansion. In mice with collagen-induced arthritis, adoptive transfer of OE-MSCs markedly suppressed arthritis onset and disease severity, which was accompanied by increased Treg cells and reduced Th1/Th17 cell responses in vivo. Taken together, our findings identified a novel function of OE-MSCs in regulating T-cell responses, indicating that OE-MSCs may represent a new cell therapy for the treatment of rheumatoid arthritis and other autoimmune diseases.

Leptin Signaling Protects NK Cells from Apoptosis During Development in Mouse Bone Marrow

Increasing evidence indicates a role of leptin in immune response, but it remains largely unclear whether leptin signaling is involved in regulating NK cell development in the bone marrow （BM）. In this study, we have characterized NK cell differentiation and maturation in the BM of leptin-receptor deficient db/db mice at a prediabetic stage. Although the BM cellularity was similar to the control value, the total number of NK cells was severely reduced in mutant mice. Flow cytometric analysis of db/db BM cells revealed significantly decreased frequencies of developing NK cells at various stages of differentiation. BM db/db NK cells displayed markedly increased apoptosis but maintained normal cell cycling status and proliferative capacity. Moreover, recombinant leptin could significantly enhance the survival of NK cells from wild-type mice in cultures. Further examination on NK cell functional activity showed that db/db NK cells exhibited normal intrinsic cytotoxicity with significantly increased IL-10 production. Taken together, our findings suggest that leptin signaling regulates NK cell development via enhancing the survival of immature NK cells in mouse BM.

APOE interacts with ACE2 inhibitingg SARS-CoV-2 cellular entry and inflammation in COVID-19 patients

Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol metabolism.The APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases.Although APOE has recently been associated with increased susceptibility to infections of several viruses,whether and how APOEand its isoforms affect SARS-CoV-2 infection remains unclear.Here,we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients.Utilizing multiple protein interaction assays,we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2;and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2,a key docking site for SARS-CoV-2 Spike protein.In addition,immuno-imaging assays using confocal,super-resolution,and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spikemediated viral entry into cells.Interestingly,while having a comparable binding affinity to ACE2,APOE4 inhibits viral entry to a lesser extent compared to APOE3,which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2.Furthermore,APOE e4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed.Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2,which may explain in part increased COVID-19 infection and disease severity in APOE e4 carriers.

An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand

Glucocorticoid-induced tumor-necrosis factor receptor(GITR)and its ligand,GITRL,play significant roles in regulating immune responses.It is clear that human soluble GITRL(hsGITRL)transduces signal activity through multiple oligomerization states.To develop human soluble trimeric GITRL protein as a potential therapeutic target,we explored the link of the isoleucine-zipper(ILZ)motif to the N-terminus of the human soluble GITRL with two leucine sequences.hsGITRL,with the ILZ motif(ILZ-hsGITRL),was firstly expressed in Escherichia coli,which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS–polyacrylamide gel electrophoresis(SDS-PAGE).The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD41 T proliferation,interferon-c(IFN-c)secretion and binding activity assay.To reveal and compare the underlying mechanisms,the level of extracellular signal-regulated kinase-1/2(ERK1/2)phosphorylation was examined,indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL.In conclusion,the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.