scholarly journals Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Hua Zhu ◽  
Zhihong Jian ◽  
Yi Zhong ◽  
Yingze Ye ◽  
Yonggang Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Tissue ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Immunofluorescence Staining ◽  
Western Blots ◽  
Stat3 Pathway ◽  
Stat3 Signaling

BackgroundInflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses via the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms.MethodsRux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice in vivo and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1β, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model in vitro.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.

scholarly journals Janus Kinase Inhibition Ameliorates Cerebral Ischemic Injury and Neuroinflammation through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

2021 ◽  
Author(s):  
Hua Zhu ◽  
Yi Zhong ◽  
Zhihong Jian ◽  
Yingze Ye ◽  
Yonggang Zhang ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Janus Kinase ◽  
Immunofluorescence Staining ◽  
Western Blots ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Inflammasome Component ◽  
Ht22 Cell

Abstract BackgroundEvidence shows that inflammatory responses play multiphasic roles in stroke pathogenesis. Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, is efficacious in COVID-19 by reducing inflammation via the JAK2/STAT3 pathway. MethodsHere, we investigated whether JAK2 inhibition has neuroprotective effects against ischemic stroke (IS) in MCAO mice in vivo and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model, and explored the potential molecular mechanisms. Rux was applied to MCAO mice. Immunofluorescence staining, RT-qPCR, and western blots were used to measure the expression of NLRP3 inflammation components and proinflammatory cytokines as well as JAK2/STAT3 pathway. Local STAT3 deficiency in brain tissue was established to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment obviously improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of NLRP3 inflammasome components, proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (p-STAT3) in neurons. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMBG1, IL-1β, IL-2, and IL-6 in middle cerebral artery occlusion (MCAO) model mice, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Local STAT3 deficiency decreased histone H3 and H4 acetylation on the NLRP3 promoter and the NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Finally, the effect of Rux on the NLRP3 inflammasome was further assessed in a HT22 cell OGD/R model in vitro. Rux application markedly suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in vitro the in OGD/R HT22 cell model.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting downstream proinflammatory cytokines and H3 and H4 acetylation on the NLRP3 promoter, resulting in downregulation of NLRP3 inflammasome component expression.

Abstract W P199: Deficiency of Glia Maturation Factor Abrogates Brain Injury and Inflammation in a Murine Model of Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Western Blots ◽  
Ischemic Brain ◽  
Maturation Factor

Background and purpose: Glia maturation factor (GMF), a brain specific protein, discovered and characterized in our laboratory, induces expression of proinflammatory cytokines/ chemokines in the central nervous system (CNS). Recently, it has been demonstrated that deficiency of GMF mitigates neuronal damage in tissue culture cell and animal models of neurodegeneration. Since, GMF expression in brain enhances inflammation; we tested the hypothesis that deficiency of GMF abrogates the inflammatory responses in experimental model of ischemic stroke. Methods: Transient focal cerebral ischemia was induced by 1 hour of occlusion of the right middle cerebral artery (MCAO) with a 7.0 monofilament in GMF-containing wild type (Wt) and GMF-deficient (GMF-KO) mice. Mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the infarct volume and estimation of inflammatory responses. Immunohistochemistry and western blots were used to analyze the expression and activation of glial cells, and levels of NF-κB in ischemic brain hemisphere. Results: We found that levels of GMF significantly increased in MCAO mice compared to saline treated control mice. Next we found that GMF-KO mice exhibited significantly decreased infarct volume, and reduced neurological deficits compared to Wt mice. The decrease in infarct volume and neurological deficits in GMF-KO mice were correlated with a less activation of glia cells, downregulation of NF-κB and suppression of proinflammatory cytokines/chemokine in the ischemic region. Conclusions: In conclusion, present study provides the first evidence that deficiency of GMF reduces brain injury and inflammation after ischemic stroke and suggests that the effective suppression of endogenous GMF-function will prove to be an effective and selective strategy to slow deleterious inflammatory processes in ischemic brain injury. Keywords: Glia maturation factor; Ischemic stroke; Inflammation; Nuclear factor-κB; Cytokines

scholarly journals Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

Abstract 5851: Activation of Inflammatory and Apoptotic Pathways in Human Donor Heart Dysfunction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christian F Bulcao ◽  
Karen M D’Souza ◽  
Ricky Malhotra ◽  
Michelle Staron ◽  
Prakash K Pandalai ◽  
...  
Keyword(s):  
Heart Disease ◽  
Structural Heart Disease ◽  
Left Ventricular ◽  
Donor Heart ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Brain Dead ◽  
Phosphorylated Stat3 ◽  
Proapoptotic Gene

Donor heart dysfunction (DHD) precluding procurement for transplantation occurs in up to 25% of brain dead donors in the absence of structural heart disease. The molecular mechanisms of DHD remain unclear. We investigated the potential role of myocardial interleukin (IL)-6 signaling through the JAK2/STAT3 pathway which leads to the generation of nitric oxide (NO) and decreased cardiac myocyte contractility in vitro. NO can also lead to induction of the proapoptotic gene Bnip3 in vitro. Hearts were procured using standard technique with UW solution from 14 brain dead donors with a left ventricular ejection fraction of < 30% (DHD) in the absence of structural heart disease. Six hearts with normal function (NF) that were procured but not transplanted for non-cardiac reasons served as controls. Left ventricular (LV) IL-6 levels were quantitated by ELISA and signaling through the JAK2/STAT3 pathway via IL-6 and gp130 receptors was assessed by expression of activated, or phosphorylated STAT3. NO signaling was measured by myocardial expression of inducible NO synthase (iNOS) and protein immunoblotting for Bnip3 was performed. Myocardial IL-6 protein levels were 8-fold greater in the DHD group vs. NF controls ( P < 0.02). Phosphorylated STAT3 expression was 5-fold higher in DHD vs. NF ( P < 0.01) indicating increased JAK2/STAT3 signaling as there was no difference in total STAT3 expression between groups ( P >0.05). LV expression of iNOS was 2-fold greater in DHD vs. NF ( P < 0.03) consistent with increased iNOS activity. In addition, LV expression of the proapoptotic gene Bnip3 was 3-fold greater in the DHD group vs. NF ( P < 0.04) suggesting that apoptosis may contribute to DHD. N= 14 for DHD and n= 6 for NF in all studies. Increased myocardial IL-6-mediated signaling through the JAK2/STAT3 pathway leading to upregulation of iNOS and NO production may be an important mechanism in human DHD. Increased myocardial NO also appears to lead to upregulation of proapoptotic Bnip3 in cardiac myocytes, and apoptotic cell death may also contribute to ventricular dysfunction following brain death. Inhibition of IL-6/JAK2/STAT3 signaling may represent a novel strategy to increase the severely limited number of cardiac donors.

scholarly journals Effect of Gold Nanoparticles on the TLR2-Mediated Inflammatory Responses Induced by Leptospira in TLR2-Overexpressed HEK293 Cells

Nanomaterials ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2522
Author(s):  
Kanidta Sooklert ◽  
Chawikan Boonwong ◽  
Pattama Ekpo ◽  
Rojrit Rojanathanes ◽  
Kanitha Patarakul ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Hek293 Cells ◽  
Infection Model ◽  
Tlr2 Expression ◽  
Inflammatory Parameters ◽  
Factor Α ◽  
20 Nm

Leptospira infection can cause potential hazards to human health by stimulating inflammation, which is mediated mainly through the Toll-like receptor 2 (TLR2) pathway. Gold nanoparticles (AuNPs) are promising for medical applications, as they display both bioinert and noncytotoxic characteristics. AuNPs have been shown to have the ability to modify immune responses. To understand the in vitro immunomodulatory effect of AuNPs in a Leptospira infection model, the activation of TLR2 expression was examined in HEK-Blue-hTLR2 cells treated with Leptospira serovars and/or AuNPs (10 and 20 nm). The ability of AuNPs to modulate an inflammatory response induced by Leptospira was examined in terms of transcript expression level modulation of three proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β and IL-6) using two-stage quantitative real-time reverse transcriptase PCR. The results revealed that the administration of 10 nm AuNPs could augment the Leptospira-induced TLR2 signaling response and upregulate the expression of all three cytokine gene transcripts, whereas the 20 nm AuNPs attenuated the TLR2 activation and expression of proinflammatory cytokines. This indicates that AuNPs can modulate inflammatory parameters in Leptospira infection and different-sized AuNPs had different immunomodulatory functions in this model.

scholarly journals CD36-Mediated Lipid Accumulation and Activation of NLRP3 Inflammasome Lead to Podocyte Injury in Obesity-Related Glomerulopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Zhao ◽  
Hong-liang Rui ◽  
Min Yang ◽  
Li-jun Sun ◽  
Hong-rui Dong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lipid Accumulation ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Animal Experiments ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Podocyte Injury ◽  
Peroxisome Proliferator Activated Receptor

Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.

scholarly journals Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Weicheng Zhao ◽  
Xiaolei Huang ◽  
Xue Han ◽  
Dan Hu ◽  
Xiaohuai Hu ◽  
...  
Keyword(s):  
Mast Cells ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Intestinal Ischemia ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Intestinal Injury ◽  
Cromolyn Sodium ◽  
Inflammasome Activation

Background. Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. Methods. Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups (n=8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. Results. Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and β-hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. Conclusions. In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction.

NLRP3 inflammasome in ischemic stroke: As possible therapeutic target

2019 ◽  
Vol 14 (6) ◽  
pp. 574-591 ◽  
Author(s):  
Masoumeh Alishahi ◽  
Maryam Farzaneh ◽  
Farhoodeh Ghaedrahmati ◽  
Armin Nejabatdoust ◽  
Alireza Sarkaki ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Receptor Protein ◽  
Current Evidence ◽  
Related Factor ◽  
Type I ◽  
Micro Rnas ◽  
Extracellular Environment ◽  
Inflammasome Inhibitors

Inflammation is a devastating pathophysiological process during stroke, a devastating disease that is the second most common cause of death worldwide. Activation of the NOD-like receptor protein (NLRP3)-infammasome has been proposed to mediate inflammatory responses during ischemic stroke. Briefly, NLRP3 inflammasome activates caspase-1, which cleaves both pro-IL-1 and pro-IL-18 into their active pro-inflammatory cytokines that are released into the extracellular environment. Several NLRP3 inflammasome inhibitors have been promoted, including small molecules, type I interferon, micro RNAs, nitric oxide, and nuclear factor erythroid-2 related factor 2 (Nrf2), some of which are potentially efficacious clinically. This review will describe the structure and cellular signaling pathways of the NLRP3 inflammasome during ischemic stroke, and current evidence for NLRP3 inflammasome inhibitors.

scholarly journals Hypoxia Induces Astrocyte-Derived Lipocalin-2 in Ischemic Stroke

2019 ◽  
Vol 20 (6) ◽  
pp. 1271 ◽  
Author(s):  
Fatemeh Ranjbar Taklimie ◽  
Natalie Gasterich ◽  
Miriam Scheld ◽  
Ralf Weiskirchen ◽  
Cordian Beyer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Proinflammatory Cytokines ◽  
Innate Immune ◽  
Fine Tuning ◽  
Lipocalin 2 ◽  
Infarct Zone ◽  
Excess Iron ◽  
Hypoxic Conditions ◽  
Tissue Degeneration

Ischemic stroke causes rapid hypoxic damage to the core neural tissue which is followed by graded chronological tissue degeneration in the peri-infarct zone. The latter process is mainly triggered by neuroinflammation, activation of inflammasomes, proinflammatory cytokines, and pyroptosis. Besides microglia, astrocytes play an important role in the fine-tuning of the inflammatory network in the brain. Lipocalin-2 (LCN2) is involved in the control of innate immune responses, regulation of excess iron, and reactive oxygen production. In this study, we analyzed LCN2 expression in hypoxic rat brain tissue after ischemic stroke and in astrocyte cell cultures receiving standardized hypoxic treatment. Whereas no LCN2-positive cells were seen in sham animals, the number of LCN2-positive cells (mainly astrocytes) was significantly increased after stroke. In vitro studies with hypoxic cultured astroglia revealed that LCN2 expression is significantly increased after only 2 h, then further increased, followed by a stepwise decline. The expression pattern of several proinflammatory cytokines mainly followed that profile in wild type (WT) but not in cultured LCN2-deficient astrocytes. Our data revealed that astrocytes are an important source of LCN2 in the peri-infarct region under hypoxic conditions. However, we must also stress that brain-intrinsic LCN2 after the initial hypoxia period might come from other sources such as invaded immune cells and peripheral organs via blood circulation. In any case, secreted LCN2 might have an influence on peripheral organ functions and the innate immune system during brain hypoxia.

scholarly journals SARS Unique Domain (SUD) of Severe Acute Respiratory Syndrome Coronavirus Induces NLRP3 Inflammasome-Dependent CXCL10-Mediated Pulmonary Inflammation

2020 ◽  
Vol 21 (9) ◽  
pp. 3179 ◽  
Author(s):  
Young-Sheng Chang ◽  
Bo-Han Ko ◽  
Jyh-Cherng Ju ◽  
Hsin-Hou Chang ◽  
Su-Hua Huang ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Profile Analysis ◽  
Diffuse Alveolar Damage ◽  
Pulmonary Inflammation ◽  
Antiviral Agents ◽  
Lung Epithelial Cells ◽  
Unique Domain

Severe acute respiratory syndrome–associated coronavirus (SARS-CoV) initiates the cytokine/chemokine storm-mediated lung injury. The SARS-CoV unique domain (SUD) with three macrodomains (N, M, and C), showing the G-quadruplex binding activity, was examined the possible role in SARS pathogenesis in this study. The chemokine profile analysis indicated that SARS-CoV SUD significantly up-regulated the expression of CXCL10, CCL5 and interleukin (IL)-1β in human lung epithelial cells and in the lung tissues of the mice intratracheally instilled with the recombinant plasmids. Among the SUD subdomains, SUD-MC substantially activated AP-1-mediated CXCL10 expression in vitro. In the wild type mice, SARS-CoV SUD-MC triggered the pulmonary infiltration of macrophages and monocytes, inducing CXCL10-mediated inflammatory responses and severe diffuse alveolar damage symptoms. Moreover, SUD-MC actuated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-dependent pulmonary inflammation, as confirmed by the NLRP3 inflammasome inhibitor and the NLRP3−/− mouse model. This study demonstrated that SARS-CoV SUD modulated NLRP3 inflammasome-dependent CXCL10-mediated pulmonary inflammation, providing the potential therapeutic targets for developing the antiviral agents.

Sign in / Sign up

Export Citation Format

Share Document