Alarmins from conjunctival fibroblasts up-regulate matrix metalloproteinases in corneal fibroblasts

AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)was prepared by subjecting human conjunctival fibroblasts to three cycles of freezing and thawing.The amounts of interleukin(IL)-1βand tumor necrosis factor(TNF)-αin NHCS were determined by enzyme-linked immunosorbent assays.HCFs exposed to NHCS or other agents in culture were assayed for the release of MMPs as well as for intracellular signaling by immunoblot analysis.The abundance of MMP m RNAs in HCFs was examined by reverse transcription and real-time polymerase chain reaction analysis.RESULTS:NHCS increased the release of MMP-1 and MMP-3 by HCFs as well as the amounts of the corresponding m RNAs in the cells.NHCS also induced activation of mitogen-activated protein kinase(MAPK)signaling pathways mediated by extracellular signal-regulated kinase(ERK),p38,and c-Jun NH2-terminal kinase(JNK)as well as elicited that of the nuclear factor(NF)-κB signaling pathway by promoting phosphorylation of the endogenous NF-κB inhibitor IκB-α.Inhibitors of MAPK and NF-κB signaling as well as IL-1 and TNF-αreceptor antagonists attenuated the NHCS-induced release of MMP-1 and MMP-3 by HCFs.Furthermore,IL-1βand TNF-αwere both detected in NHCS,and treatment of HCFs with these cytokines induced the release of MMP-1 and MMP-3 in a concentration-dependent manner.CONCLUSION:Alarmins,including IL-1βand TNF-α,produced by necrotic human conjunctival fibroblasts triggered MMP release in HCFs through activation of MAPK and NF-κB signaling.IL-1βand TNF-αare therefore potential therapeutic targets for the amelioration of corneal stromal degradation in severe ocular burns.

Hepatic Alarmins and Mitochondrial Dysfunction under Residual Hyperlipidemic Stress Lead to Irreversible NAFLD

Background and Aims:Nonalcoholic fatty liver disease(NAFLD)includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis.We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.Methods:The effect of combined lipid-lowering drugs(statins and anti-PCSK9 monoclonal antibody)were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators,such as alarmins,responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.Results:Proteomic analysis revealed a number of proteins whose abundance was altered.They were components of metabolic pathways including fatty-acid degradation,glycolysis/gluconeogenesis,and nonalcoholic fatty liver disease.Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH:ubiquinone oxidoreductase.The expression of a majority of cytochromes(P4502E1,b5,and c)were up-regulated by lipid-lowering treatment.Long-term hyperlipidemic stress,even with a low-fat diet and lipid-lowering treatment,was accompanied by alarmin release(annexins,galectins,HSPs,HMGB1,S100 proteins,calreticulin,and fibronectin)that generated local inflammation and induced liver steatosis and aggressive fibrosis(by high abundance of galectin 3,fibronectin,and calreticulin).Conclusions:The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent,combined lipid-lowering treatment with statin and inhibitor of PCSK9.

HMGB1, IL-1α, IL-33 and S100 proteins： dual-function alarmins

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

Contributions of the receptor for advanced glycation end products axis activation in gastric cancer

Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products(RAGE)axis activation in the development of neoplasms,including gastric cancer(GC).This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu,not only by supporting phenotypic changes favoring growth and dissemination of tumor cells,but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection.In the present review,we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis.Finally,the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.

Receptor for advanced glycation end-products axis and coronavirus disease 2019 in inflammatory bowel diseases:A dangerous liaison?

Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection.In the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)2.The soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.

Inflammatory niche:Mesenchymal stromal cell priming by soluble mediators

Mesenchymal stromal/stem cells(MSCs)are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages.They play a critical role in tissue homeostasis and wound healing,as well as in regulating the inammatory microenvironment through interactions with immune cells.Hence,MSCs have garnered great attention as promising candidates for tissue regeneration and cell therapy.Because the inflammatory niche plays a key role in triggering the reparative and immunomodulatory functions of MSCs,priming of MSCs with bioactive molecules has been proposed as a way to foster the therapeutic potential of these cells.In this paper,we review how soluble mediators of the inflammatory niche(cytokines and alarmins)influence the regenerative and immunomodulatory capacity of MSCs,highlighting the major advantages and concerns regarding the therapeutic potential of these inflammatory primed MSCs.The data summarized in this review may provide a significant starting point for future research on priming MSCs and establishing standardized methods for the application of preconditioned MSCs in cell therapy.

Hip prosthetic loosening and periprosthetic osteolysis:A commentary

Prosthetic loosening and periprosthetic osteolysis have been debated for decades,both in terms of the timing and nature of the triggering events.The hypothesis of wear-particle-induced loosening states that wear particles cause a foreign-body response leading to periprosthetic osteolysis and ultimately to late prosthetic loosening,i.e.,that the osteolysis precedes the loosening.The theory of early loosening,on the other hand,postulates that the loosening is already initiated during or shortly after surgery,i.e.,that the osteolysis is secondary to the loosening.This commentary focuses on the causal relationship between prosthetic loosening and periprosthetic osteolysis.

Advanced-glycation end-products axis:A contributor to the risk of severe illness from COVID-19 in diabetes patients

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products(RAGE)in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus(DM).During the coronavirus disease 2019(COVID-19)pandemic,many clinical reports have pointed out that DM increases the risk of COVID-19 complications,hospitalization requirements,as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate.In the present review,we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype,as well as the contribution of RAGE signaling in lung inflammation,may then lead to the increased mortality risk of COVID-19 in these patients.Additionally,the crosstalk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection,as well as the role of this multi-ligand receptor on the obesity-associated lowgrade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19,are also discussed.

损伤相关分子模式与炎症反应

为辨别自身细胞的存活或识别微生物的入侵，多细胞动物已经进化出免疫监视、防御、修复机制。然而，目前仍不完全清楚这些机制是如何启动和协调配合的。因此，我们对相关基础研究和医疗研究现状做一个综述。