scholarly journals Interleukin-6 via Toll-Like Receptor 3 Signaling Attenuates the Expression of Proinflammatory Chemokines in Human Podocytes

2021 ◽  
Vol 46 (2) ◽  
pp. 207-218
Author(s):  
Hidenori Umetsu ◽  
Shojiro Watanabe ◽  
Tadaatsu Imaizumi ◽  
Tomomi Aizawa ◽  
Koji Tsugawa ◽  
...  
Keyword(s):  
Rna Interference ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Induced Expression ◽  
Inflammatory Reactions ◽  
Monocyte Chemoattractant Protein 1 ◽  
Polycytidylic Acid ◽  
Tlr3 Signaling

<b><i>Background:</i></b> Although toll-like receptor 3 (TLR3) signaling is involved in the development of certain chronic kidney diseases, the specific molecular mechanisms underlying inflammatory reactions via activation of TLR3 signaling in human podocytes remain unclear. Interleukin (IL)-6 is a pleiotropic cytokine associated with innate and adaptive immune responses; however, little is known about the implication of IL-6 via the activation of regional TLR3 signaling in the inflammatory reactions in human podocytes. <b><i>Methods:</i></b> We treated immortalized human podocytes with polyinosinic-polycytidylic acid (poly IC), an authentic viral double-stranded RNA, and assessed the expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), and C-C motif chemokine ligand 5 (CCL5) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. To further elucidate the poly IC-induced signaling pathway, we subjected the cells to RNA interference against IFN-β and IL-6. <b><i>Results:</i></b> We found that the activation of TLR3 induced expression of IL-6, MCP-1, CCL5, and IFN-β in human podocytes. RNA interference experiments revealed that IFN-β was involved in the poly IC-induced expression of IL-6, MCP-1, and CCL5. Interestingly, IL-6 knockdown markedly increased the poly IC-induced expression of MCP-1 and CCL5. Further, treatment of cells with IL-6 attenuated the expression of CCL5 and MCP-1 mRNA and proteins. <b><i>Conclusion:</i></b> IL-6 induced by TLR3 signaling negatively regulates the expression of representative TLR3 signaling-dependent proinflammatory chemokines in human podocytes.

scholarly journals Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes

2021 ◽  
Author(s):  
Tatsuro Saruga ◽  
Tadaatsu Imaizumi ◽  
Shogo Kawaguchi ◽  
Kazuhiko Seya ◽  
Tomoh Matsumiya ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Neutralizing Antibody ◽  
Poly I:C ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Inflammatory Reactions ◽  
Polyinosinic:Polycytidylic Acid ◽  
Tlr3 Signaling ◽  
Fibroblast Like Synoviocytes

AbstractC-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.

scholarly journals Cytosolic Sensors of Viral RNA Are Involved in the Production of Interleukin-6 via Toll-Like Receptor 3 Signaling in Human Glomerular Endothelial Cells

2019 ◽  
Vol 44 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Qiang Liu ◽  
Tadaatsu Imaizumi ◽  
Tomomi Aizawa ◽  
Koji Hirono ◽  
Shogo Kawaguchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Interleukin 6 ◽  
Viral Rna ◽  
Pivotal Role ◽  
Toll Like Receptor ◽  
Polycytidylic Acid ◽  
Glomerular Endothelial Cells ◽  
Human Glomerular Endothelial Cells ◽  
Tlr3 Signaling

Background/Aims: Dysregulation of interleukin-6 (IL-6) production in residual renal cells may play a pivotal role in the development of glomerulonephritis (GN). Given that Toll-like receptor 3 (TLR3) signaling has been implicated in the pathogenesis of some forms of GN, we examined activated TLR3-mediated IL-6 signaling in cultured normal human glomerular endothelial cells (GECs). Methods: We treated GECs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of IL-6 and the cytosolic viral RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) using reverse transcription quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays. To further elucidate the effects of poly IC on this signaling pathway, we subjected the cells to small interfering RNA (siRNA) against TLR3, interferon (IFN)-β, RIG-I, and MDA5. Results: We found that poly IC induced the expression of RIG-I, MDA5 and IL-6 via TLR3/IFN-β signaling in GECs. siRNA experiments revealed that both MDA5 and RIG-I were involved in the poly IC-induced expression of IL-6, with MDA5 being upstream of RIG-I. Conclusion: Interestingly, cytosolic sensors of viral RNA were found to be involved in IL-6 production via TLR3 signaling in GECs. Regional activation of TLR3/IFN-β/ MDA5/RIG-I/IL-6 axis due to viral and “pseudoviral” infections is involved in innate immunity and inflammatory reactions in GECs. We believe this signaling pathway also plays a pivotal role in the development of some forms of GN.

P1800RITUXIMAB ENHANCES THE EXPRESSION OF INTERLEUKIN-6 VIA TOLL-LIKE RECEPTOR 3 SIGNALING IN HUMAN PODOCYTE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Shojiro Watanabe ◽  
Koji Hirono ◽  
Tomomi Aizawa ◽  
Koji Tsugawa ◽  
Hiroshi Tanaka
Keyword(s):  
Nephrotic Syndrome ◽  
B Cell ◽  
Peripheral Blood ◽  
Sustained Remission ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Cell Recovery ◽  
Viral Dsrna ◽  
Polycytidylic Acid ◽  
Tlr3 Signaling

Abstract Background and Aims The etiology of idiopathic nephrotic syndrome (INS) in children remains unclear, but it is well known that viral infections often cause relapses of INS. Since toll-like receptor 3 (TLR3), a ligand of viral dsRNA exists in podocytes, dysregulation of TLR3 signaling in podocytes may be involved in the pathogenesis of INS. Recently, rituximab (RTX) a specific antibody to human CD20, has been successfully used to treat children with intractable nephrotic syndrome (frequent relapse nephrotic syndrome, FRNS, and steroid dependent nephrotic syndrome, SDNS). It has been reported that depletion of B cell is main mechanism of RTX treatment. However, some patients experienced recurrence before peripheral blood B cell recovery, whereas selected patients have sustained remission even after peripheral blood B cell recovery. Considering that dramatic effects of RTX in the treatment of INS, it is speculated that some B cell-independent mechanisms of RTX exist. In this context, some recent studies have reported a direct effect of RTX on podocyte, targeting sphingomyelinase phosphodiesterase acid-like 3b (SMPDL3b), but detailed mechanisms remain to be determined. In this study, we examined whether RTX influences TLR3 signaling in cultured human podocyte. Method Immortalized human podocytes in culture were treated with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of viral dsRNA. RTX were added before or after the treatment of poly IC. Then, expression of interleukin (IL)-6 were measured using real time RT-PCR and ELISA. Direct binding of RTX to podocyte were confirmed by immunofluorescence. Results Poly IC induced the expression of IL-6 in cultured human podocyte in a concentration and time-dependent manner. IL-6 expression induced by poly IC were enhanced in both mRNA and protein level by pretreatment of RTX. RTX itself were apparently stained on podocyte by immunofluorescence. Conclusion RTX binds directly to cultured human podocyte and enhances the IL-6 expression induced by poly IC. Since IL-6 from podocyte was reported to be engaged in regulating glomerular inflammation by cross-talk with endothelial cells, exploring the role of enhanced IL-6 from podocyte by RTX, at least in a part, suggests a direct mechanism of RTX in treating intractable nephrotic syndrome in children.

scholarly journals Statins attenuate antiviral IFN-β and ISG expression via inhibiting IRF3/JAK/STAT signaling in poly(I:C)-treated hyperlipidemic mice and macrophages

2020 ◽  
Author(s):  
Atsushi Koike ◽  
Kaito Tsujinaka ◽  
Ko Fujimori
Keyword(s):  
Bronchoalveolar Lavage ◽  
Molecular Mechanisms ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Janus Kinase ◽  
Poly I:C ◽  
Induced Expression ◽  
Antiviral Immune Response ◽  
Polycytidylic Acid ◽  
Stat Signaling

AbstractViral infection is a significant burden to healthcare worldwide. Statins, 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, are widely used as cholesterol-lowering drugs. Recently, long term statin therapy was shown to reduce the antiviral immune response; however, the underlying molecular mechanisms are unclear. Here, we found that simvastatin decreased polyinosinic-polycytidylic acid [poly(I:C)]-induced expression of antiviral interferon (IFN)-β and IFN-stimulated genes (ISGs) in the bronchoalveolar lavage fluid and lungs of mice with high-fat diet-induced hyperlipidemia. As macrophages were the dominant cell type in the bronchoalveolar lavage fluid of poly(I:C)-treated mice, we examined the molecular mechanisms of statin-mediated inhibition of antiviral gene expression using murine J774.1/JA-4 macrophages. Simvastatin and pitavastatin decreased poly(I:C)-induced expression of IFN-β and ISGs. Moreover, they repressed poly(I:C)-induced phosphorylation of IFN regulatory factor (IRF) 3 and signal transducers and activators of transcription (STAT) 1, which is involved in Janus kinase (JAK)/STAT signaling. Mevalonate and geranylgeranylpyrophosphate (GGPP), but not cholesterol, counteracted the negative effect of statins on IFN-β and ISG expression and phosphorylation of IRF3 and STAT1. These results suggest that statins suppressed the expression of IFN-β and ISGs in poly(I:C)-treated hyperlipidemic mice and murine macrophages, and that these effects occured through the inhibition of IRF3-mediated JAK/STAT signaling in macrophages. Furthermore, GGPP recovered the statin-suppressed IRF3/JAK/STAT signaling pathway in poly(I:C)-treated macrophages.

scholarly journals Impaired trophoblast Toll-Like Receptor 3 signaling pathway involves in hepatitis B vaccine non- or hypo-response of infants born to HBsAg-positive mothers

2020 ◽  
Author(s):  
Lina Wu ◽  
Ruijun Zhang ◽  
Yongliang Feng ◽  
Tian Yao ◽  
Linzhu Yi ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Signaling Pathway ◽  
Hepatitis B Surface Antigen ◽  
Quantitative Polymerase Chain Reaction ◽  
Hbv Dna ◽  
Enzyme Linked Immunosorbent Assay ◽  
Toll Like Receptor ◽  
Insufficient Response ◽  
Hb Vaccine ◽  
Tlr3 Signaling

Abstract Background: Babies born to hepatitis B surface antigen (HBsAg) positive mothers bear a high risk of being non- or hypo-responsive to hepatitis B (HB) vaccine with unilluminated mechanisms. Placental immunity is closely related to the development of baby immune system, however, the roles of the placental immunity in the insufficient response of these babies are unclear. This study was aimed to investigate the role of placental trophoblast Toll-Like Receptor 3（TLR3）signaling pathway in HB vaccine non- or hypo-response of these special babies. Methods: A total of 399 pairs of HBsAg-positive mothers and their neonates were recruited to perform a nested case-control study. The maternal and children’s HBV DNA and the HBV serological markers were detected by Fluorescence Quantitative Polymerase Chain Reaction (FQ-PCR) and Electrochemiluminescence Immunoassay (ECLIA). The trophoblast TLR3 signaling pathway proteins and infant cytokines IL-6, IL-12, TNF-α, IFN-α and IFN-γ were tested by immunohistochemistry (IHC) and Enzyme–Linked Immunosorbent Assay (ELISA). Results: The expression of TLR3 and NF-κB, a TLR3 downstream protein, were significantly decreased in the non- or hypo-responders ( Z= -3.00 and -2.46, P <0.01 and =0.01). Furthermore, the trophoblast TLR3 expression negatively correlated with maternal HBV DNA ( r = -0.29, P = 0.003), HBeAg ( r = -0.28, P = 0.01) and HBV DNA+HBeAg ( r = -0.24, P = 0.02). Besides, NF-κB positively correlated with infant IL-6 ( r = 0.24, P = 0.026). By comprehensive analysis of maternal, placental and infant information, a Bayesian network model showed that the trophoblast TLR3 signaling pathway contacted with the non- or hypo-responsiveness. onclusions: Maternal HBV infection affected the trophoblast TLR3 signaling pathway protein expression, and consequently the impaired TLR3 signaling pathway involved in the HB vaccine non- or hypo-responsiveness mainly by influencing infant IL-6.

scholarly journals Infection of Mast Cells with Live Streptococci Causes a Toll-Like Receptor 2- and Cell-Cell Contact-Dependent Cytokine and Chemokine Response

2009 ◽  
Vol 78 (2) ◽  
pp. 854-864 ◽  
Author(s):  
Elin Rönnberg ◽  
Bengt Guss ◽  
Gunnar Pejler
Keyword(s):  
Mast Cells ◽  
Bacterial Infection ◽  
Molecular Mechanisms ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Contact ◽  
Toll Like Receptor ◽  
Gram Positive ◽  
Toll Like Receptor 2 ◽  
Cell Cell

ABSTRACT Mast cells (MCs) are strongly implicated in immunity toward bacterial infection, but the molecular mechanisms by which MCs contribute to the host response are only partially understood. We addressed this issue by examining the direct effects of a Gram-positive pathogen, Streptococcus equi, on bone marrow-derived MCs (BMMCs). Ultrastructural analysis revealed extensive formation of dilated rough endoplasmic reticulum in response to bacterial infection, indicating strong induction of protein synthesis. However, the BMMCs did not show signs of extensive degranulation, and this was supported by only slow release of histamine in response to infection. Coculture of live bacteria with BMMCs caused a profound secretion of CCL2/MCP-1, CCL7/MCP-3, CXCL2/MIP-2, CCL5/RANTES, interleukin-4 (IL-4), IL-6, IL-12, IL-13, and tumor necrosis factor alpha, as shown by antibody-based cytokine/chemokine arrays and/or enzyme-linked immunosorbent assay. In contrast, heat-inactivated bacteria caused only minimal cytokine/chemokine release. The cytokine/chemokine responses were substantially attenuated in Toll-like receptor 2-deficient BMMCs and were strongly dependent on cell-cell contacts between bacteria and BMMCs. Gene chip microarray analysis confirmed a massively upregulated expression of the genes coding for the secreted cytokines and chemokines and also identified a pronounced upregulation of numerous additional genes, including transcription factors, signaling molecules, and proteases. Together, the present study outlines MC-dependent molecular events associated with Gram-positive infection and thus provides an advancement in our understanding of how MCs may contribute to host defense toward bacterial insults.

Fc receptor γ-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3623-3632 ◽  
Author(s):  
Estelle Merck ◽  
Blandine de Saint-Vis ◽  
Mathieu Scuiller ◽  
Claude Gaillard ◽  
Christophe Caux ◽  
...  
Keyword(s):  
T Cells ◽  
Fc Receptor ◽  
Poly I:C ◽  
Toll Like Receptor ◽  
Phosphatidylinositol 3 Kinase ◽  
Monocyte Chemoattractant Protein 1 ◽  
Polycytidylic Acid ◽  
Extracellular Signal ◽  
Chemokine Ligand ◽  
Human Osteoclast

AbstractWe previously reported the characterization of human osteoclast-associated receptor (hOSCAR), a novel Fc receptor γ-chain (FcRγ)–associated receptor expressed by myeloid cells. Here we show that ligation of hOSCAR by specific antibodies promotes dendritic cell (DC) survival by an extracellular signal-regulated kinase (ERK)- and phosphatidylinositol 3-kinase (PI3K)–dependent pathway, linked to expression of the Bcl-2 and Bcl-xL antiapoptotic molecules. Crosslinking of hOSCAR leads to maturation of DCs, as demonstrated by up-regulation of maturation markers, decrease in dextran uptake capacity, and secretion of immunesystem effectors such as interleukin-8 (IL-8)/CXC chemokine ligand 8 (CXCL8), IL-12 p40, monocyte chemoattractant protein-1 (MCP-1)/chemokine receptor ligand 2 (CCL2) and macrophage-derived chemokine (MDC)/CCL22. Stimulation of hOSCAR acts in conjunction with the Toll-like receptor (TLR) ligands, lipopolysaccharide (LPS), R-848, and polyinosinic-polycytidylic acid (poly(I:C)), to increase the expression of maturation markers, and to modulate cytokine release. A PI3K-dependent up-regulation of IL-10 release is observed with all the TLR ligands used, whereas regulation of IL-12 production is variable depending on the TLR stimulated. hOSCAR engagement on DCs did not significantly increase the proliferation of naive T cells; however, when co-incubated with TLR ligands, an enhanced proliferation was observed. The percentage of interferon (IFN)–γ–producing T cells is decreased when hOSCAR engagement is combined with LPS stimulation. Altogether, these data suggest that hOSCAR may modulate the responses of both innate resistance and adaptive immunity.

scholarly journals Regulatory Roles of Osteopontin in Production of Monocyte-Origin MCP-1

2018 ◽  
Vol 27 (8) ◽  
pp. 1185-1194
Author(s):  
Liying Shi ◽  
Lin Shi ◽  
Xiangdong Wang ◽  
Jiantai He
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Inflammatory Cells ◽  
Underlying Mechanism ◽  
Leukocyte Migration ◽  
Enzyme Linked Immunosorbent Assay ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Migration ◽  
Molecular Events

Osteopontin (OPN), expressed by various immune cells, plays a critical role in leukocyte migration. Although OPN was found to selectively induce the expression of proinflammatory chemokines, the molecular mechanisms that control OPN gene expression and its underlying mechanism for migration and recruitment of inflammatory cells remain largely unknown. In this study, real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to determine OPN and monocyte chemoattractant protein 1 (MCP-1) expression. Signaling and molecular events between OPN and MCP-1 were analyzed by Western blot. Leukocyte migration in the presence of OPN was measured by chemotaxis assay. Our data indicated that phosphoinositide 3-kinase (PI3K), c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) that are activated upon stimulation with lipopolysaccharide were shown to upregulate OPN expression. Endogenous production of OPN was attributable to increased production of MCP-1, and this effect could be blocked by an anti-β1 integrin antibody and JNK and p38 kinase inhibitors. Furthermore, we found that the effect of OPN on inflammatory cell migration was mediated through inducing the expression of MCP-1 in monocytes. These results support a role of OPN in monocyte migration via MCP-1, which may represent an additional mechanism for innate and adaptive immune responses.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

scholarly journals Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuefei Jin ◽  
Wangquan Ji ◽  
Haiyan Yang ◽  
Shuaiyin Chen ◽  
Weiguo Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Endothelial Activation ◽  
World Health ◽  
Therapeutic Approaches ◽  
Inflammatory Reactions ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Implications ◽  
Endothelial Inflammation ◽  
The World ◽  
Health Organization

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

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