共查询到20条相似文献,搜索用时 15 毫秒
1.
Gunlg Rasmussen Berhane Asfaw Idosa Anders Bckman Stefan Monecke Kristoffer Strlin Eva Srndahl Bo Sderquist 《Microbiology and immunology》2019,63(12):487-499
The inflammasome is a multiprotein complex that mediates caspase‐1 activation with subsequent maturation of the proinflammatory cytokines IL‐1β and IL‐18. The NLRP3 inflammasome is known to be activated by Staphylococcus aureus, one of the leading causes of bacteremia worldwide. Inflammasome activation and regulation in response to bacterial infection have been found to be of importance for a balanced host immune response. However, inflammasome signaling in vivo in humans initiated by S. aureus is currently sparsely studied. This study therefore aimed to investigate NLRP3 inflammasome activity in 20 patients with S. aureus bacteremia (SAB), by repeated measurement during the first week of bacteremia, compared with controls. Caspase‐1 activity was measured in monocytes and neutrophils by flow cytometry detecting FLICA (fluorescent‐labeled inhibitor of caspase‐1), while IL‐1β and IL‐18 was measured by Luminex and ELISA, respectively. As a measure of inflammasome priming, messenger RNA (mRNA) expression of NLRP3, CASP1 (procaspase‐1), and IL1B (pro‐IL‐1β) was analyzed by quantitative PCR. We found induced caspase‐1 activity in innate immune cells with subsequent release of IL‐18 in patients during the acute phase of bacteremia, indicating activation of the inflammasome. There was substantial interindividual variation in caspase‐1 activity between patients with SAB. We also found an altered inflammasome priming with low mRNA levels of NLRP3 accompanied by elevated mRNA levels of IL1B. This increased knowledge of the individual host immune response in SAB could provide support in the effort to optimize management and treatment of each individual patient. 相似文献
2.
Julien Pothlichet Isabelle Meunier Beckley K. Davis Jenny P-Y. Ting Emil Skamene Veronika von Messling Silvia M. Vidal 《PLoS pathogens》2013,9(4)
Influenza A virus (IAV) triggers a contagious and potentially lethal respiratory disease. A protective IL-1β response is mediated by innate receptors in macrophages and lung epithelial cells. NLRP3 is crucial in macrophages; however, which sensors elicit IL-1β secretion in lung epithelial cells remains undetermined. Here, we describe for the first time the relative roles of the host innate receptors RIG-I (DDX58), TLR3, and NLRP3 in the IL-1β response to IAV in primary lung epithelial cells. To activate IL-1β secretion, these cells employ partially redundant recognition mechanisms that differ from those described in macrophages. RIG-I had the strongest effect through a MAVS/TRIM25/Riplet–dependent type I IFN signaling pathway upstream of TLR3 and NLRP3. Notably, RIG-I also activated the inflammasome through interaction with caspase 1 and ASC in primary lung epithelial cells. Thus, NS1, an influenza virulence factor that inhibits the RIG-I/type I IFN pathway, strongly modulated the IL-1β response in lung epithelial cells and in ferrets. The NS1 protein derived from a highly pathogenic strain resulted in increased interaction with RIG-I and inhibited type I IFN and IL-1β responses compared to the least pathogenic virus strains. These findings demonstrate that in IAV-infected lung epithelial cells RIG-I activates the inflammasome both directly and through a type I IFN positive feedback loop. 相似文献
3.
《Journal of molecular recognition : JMR》2017,30(9)
Inflammasomes are multiprotein caspase‐activating complexes that enhance the maturation and release of proinflammatory cytokines (IL‐1β and IL‐18) in response to the invading pathogen and/or host‐derived cellular stress. These are assembled by the sensory proteins (viz NLRC4, NLRP1, NLRP3, and AIM‐2), adaptor protein (ASC), and effector molecule procaspase‐1. In NLRP3‐mediated inflammasome activation, ASC acts as a mediator between NLRP3 and procaspase‐1 for the transmission of signals. A series of homotypic protein‐protein interactions (NLRP3PYD:ASCPYD and ASCCARD:CASP1CARD) propagates the downstream signaling for the production of proinflammatory cytokines. Pyrin‐only protein 1 (POP1) is known to act as the regulator of inflammasome. It modulates the ASC‐mediated inflammasome assembly by interacting with pyrin domain (PYD) of ASC. However, despite similar electrostatic surface potential, the interaction of POP1 with NLRP3PYD is obscured till date. Herein, to explore the possible PYD‐PYD interactions between NLRP3PYD and POP1, a combined approach of protein‐protein docking and molecular dynamics simulation was adapted. The current study revealed that POP1's type‐Ia interface and type‐Ib interface of NLRP3PYD might be crucial for 1:1 PYD‐PYD interaction. In addition to type‐I mode of interaction, we also observed type‐II and type‐III interaction modes in two different dynamically stable heterotrimeric complexes (POP1‐NLRP3‐NLRP3 and POP1‐NLRP3‐POP1). The inter‐residual/atomic distance calculation exposed several critical residues that possibly govern the said interaction, which need further investigation. Overall, the findings of this study will shed new light on hitherto concealed molecular mechanisms underlying NLRP3‐mediated inflammasome, which will have strong future therapeutic implications. 相似文献
4.
Fusobacterium nucleatum infection of gingival epithelial cells leads to NLRP3 inflammasome‐dependent secretion of IL‐1β and the danger signals ASC and HMGB1 下载免费PDF全文
Fiona Q. Bui Larry Johnson Shu‐Chen Hung Jungnam Lee Kalina Rosenova Atanasova Pei‐Rong Huang David M. Ojcius 《Cellular microbiology》2016,18(7):970-981
Fusobacterium nucleatum is an invasive anaerobic bacterium that is associated with periodontal disease. Previous studies have focused on virulence factors produced by F. nucleatum, but early recognition of the pathogen by the immune system remains poorly understood. Although an inflammasome in gingival epithelial cells (GECs) can be stimulated by danger‐associated molecular patterns (DAMPs) (also known as danger signals) such as ATP, inflammasome activation by this periodontal pathogen has yet to be described in these cells. This study therefore examines the effects of F. nucleatum infection on pro‐inflammatory cytokine expression and inflammasome activation in GECs. Our results indicate that infection induces translocation of NF‐κB into the nucleus, resulting in cytokine gene expression. In addition, infection activates the NLRP3 inflammasome, which in turn activates caspase‐1 and stimulates secretion of mature IL‐1β. Unlike other pathogens studied until now, F. nucleatum activates the inflammasome in GECs in the absence of exogenous DAMPs such as ATP. Finally, infection promotes release of other DAMPs that mediate inflammation, such as high‐mobility group box 1 protein and apoptosis‐associated speck‐like protein, with a similar time‐course as caspase‐1 activation. Thus, F. nucleatum expresses the pathogen‐associated molecular patterns necessary to activate NF‐κB and also provides an endogenous DAMP to stimulate the inflammasome and further amplify inflammation through secretion of secondary DAMPs. 相似文献
5.
LPS targets host guanylate‐binding proteins to the bacterial outer membrane for non‐canonical inflammasome activation 下载免费PDF全文
José Carlos Santos Mathias S Dick Brice Lagrange Daniel Degrandi Klaus Pfeffer Masahiro Yamamoto Etienne Meunier Pawel Pelczar Thomas Henry Petr Broz 《The EMBO journal》2018,37(6)
Pathogenic and commensal Gram‐negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase‐11 non‐canonical inflammasome. Here, we show that OMV‐induced inflammasome activation requires TLR4‐TRIF signaling, the production of type I interferons, and the action of guanylate‐binding proteins (GBPs), both in macrophages and in vivo. Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram‐negative bacterial outer membranes is LPS itself. Our findings provide new insights into the mechanism by which GBPs target foreign surfaces and reveal a novel function for GBPs in controlling the intracellular detection of LPS derived from extracellular bacteria in the form of OMVs, thus extending their function as a hub between cell‐autonomous immunity and innate immunity. 相似文献
6.
Tera C. Levin Katherine E. Wickliffe Stephen H. Leppla Mahtab Moayeri 《Cellular microbiology》2008,10(12):2434-2446
Anthrax lethal toxin (LT) rapidly kills macrophages from certain mouse strains in a mechanism dependent on the breakdown of unknown protein(s) by the proteasome, formation of the Nalp1b (NLRP1b) inflammasome and subsequent activation of caspase‐1. We report that heat‐shocking LT‐sensitive macrophages rapidly protects them against cytolysis by inhibiting caspase‐1 activation without upstream effects on LT endocytosis or cleavage of the toxin's known cytosolic substrates (mitogen‐activated protein kinases). Heat shock protection against LT occurred through a mechanism independent of de novo protein synthesis, HSP90 activity, p38 activation or proteasome inhibition and was downstream of mitogen‐activated protein kinase cleavage and degradation of an unknown substrate by the proteasome. The heat shock inhibition of LT‐mediated caspase‐1 activation was not specific to the Nalp1b (NLRP1b) inflammasome, as heat shock also inhibited Nalp3 (NLRP3) inflammasome‐mediated caspase‐1 activation in macrophages. We found that heat shock induced pro‐caspase‐1 association with a large cellular complex that could prevent its activation. Additionally, while heat‐shocking recombinant caspase‐1 did not affect its activity in vitro, lysates from heat‐shocked cells completely inhibited recombinant active caspase‐1 activity. Our results suggest that heat shock inhibition of active caspase‐1 can occur independently of an inflammasome platform, through a titratable factor present within intact, functioning heat‐shocked cells. 相似文献
7.
Stphanie Bouillot Stphane Pont Benoit Gallet Christine Moriscot Vincent Deruelle Ina Attre Philippe Huber 《Cellular microbiology》2020,22(11)
During acute Pseudomonas aeruginosa infection, the inflammatory response is essential for bacterial clearance. Neutrophil recruitment can be initiated following the assembly of an inflammasome within sentinel macrophages, leading to activation of caspase‐1, which in turn triggers macrophage pyroptosis and IL‐1β/IL‐18 maturation. Inflammasome formation can be induced by a number of bacterial determinants, including Type III secretion systems (T3SSs) or pore‐forming toxins, or, alternatively, by lipopolysaccharide (LPS) via caspase‐11 activation. Surprisingly, previous studies indicated that a T3SS‐induced inflammasome increased pathogenicity in mouse models of P. aeruginosa infection. Here, we investigated the immune reaction of mice infected with a T3SS‐negative P. aeruginosa strain (IHMA879472). Virulence of this strain relies on ExlA, a secreted pore‐forming toxin. IHMA879472 promoted massive neutrophil infiltration in infected lungs, owing to efficient priming of toll‐like receptors, and thus enhanced the expression of inflammatory proteins including pro‐IL‐1β and TNF‐α. However, mature‐IL‐1β and IL‐18 were undetectable in wild‐type mice, suggesting that ExlA failed to effectively activate caspase‐1. Nevertheless, caspase‐1/11 deficiency improved survival following infection with IHMA879472, as previously described for T3SS+ bacteria. We conclude that the detrimental effect associated with the ExlA‐induced inflammasome is probably not due to hyperinflammation, rather it stems from another inflammasome‐dependent process. 相似文献
8.
McCoy AJ Koizumi Y Higa N Suzuki T 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(11):7077-7084
Aeromonas spp. are Gram-negative bacteria that cause serious infectious disease in humans. Such bacteria have been shown to induce apoptosis in infected macrophages, yet the host responses triggered by macrophage death are largely unknown. In this study, we demonstrate that the infection of mouse bone marrow-derived macrophages with Aeromonas veronii biotype sobria triggers activation of caspase-1 with the ensuing release of IL-1β and pyroptosis. Caspase-1 activation in response to A. veronii infection requires the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain and both the NLRP3 and NLRC4 inflammasomes. Furthermore, caspase-1 activation requires aerolysin and a functional type III secretion system in A. veronii. Aerolysin-inducing caspase-1 activation is mediated through the NLRP3 inflammasome, with aerolysin-mediated cell death being largely dependent on the NLRP3 inflammasome. In contrast, the type III secretion system activates both the NLRP3 and NLRC4 inflammasomes. Inflammasome-mediated caspase-1 activation is also involved in host defenses against systemic A. veronii infection in mice. Our results indicated that multiple factors from both the bacteria and the host play a role in eliciting caspase-1 activation during A. veronii infection. 相似文献
9.
Gypenosides improve diabetic cardiomyopathy by inhibiting ROS‐mediated NLRP3 inflammasome activation 下载免费PDF全文
Hailong Zhang Xi Chen Beibei Zong Hongmin Yuan Zhizeng Wang Yinxiang Wei Xuance Wang Guangchao Liu Jun Zhang Shulian Li Guanchang Cheng Yaohui Wang Yuanfang Ma 《Journal of cellular and molecular medicine》2018,22(9):4437-4448
NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti‐hyperglycaemia and anti‐inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL‐1β and IL‐18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down‐regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C‐reactive proteins (CRPs), IL‐1β and IL‐18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS‐mediated NLRP3 inflammasome activation. 相似文献
10.
Bibhuti B. Mishra Pedro Moura‐Alves Avinash Sonawane Nir Hacohen Gareth Griffiths Luis F. Moita Elsa Anes 《Cellular microbiology》2010,12(8):1046-1063
Interleukin‐1β (IL‐1β) represents one of the most important mediators of inflammation and host responses to infection. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, induces IL‐1β secretion at the site of infection, but the underlying mechanism(s) are poorly understood. In this work we show that Mtb infection of macrophages stimulates caspase‐1 activity and promotes the secretion of IL‐1β. This stimulation requires live intracellular bacteria expressing a functional ESX‐1 secretion system. ESAT‐6, an ESX‐1 substrate implicated in membrane damage, is both necessary and sufficient for caspase‐1 activation and IL‐1β secretion. ESAT‐6 promotes the access of other immunostimulatory agents such as AG85 into the macrophage cytosol, indicating that this protein may contribute to caspase‐1 activation largely by perturbing host cell membranes. Using a high‐throughput shRNA‐based screen we found that numerous NOD‐like receptors (NLRs) and CARD domain‐containing proteins (CARDs) were important for IL‐1β secretion upon Mtb infection. Most importantly, NLRP3, ASC and caspase‐1 form an infection‐inducible inflammasome complex that is essential for IL‐1β secretion. In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT‐6, and the subsequent IL‐1β response is regulated by a number of NLR/CARD proteins. 相似文献
11.
Masahiro Okada Atsushi Matsuzawa Akihiko Yoshimura Hidenori Ichijo 《The Journal of biological chemistry》2014,289(47):32926-32936
Lysosome rupture triggers NLRP3 inflammasome activation in macrophages. However, the underlying mechanism is not fully understood. Here we showed that the TAK1-JNK pathway, a MAPK signaling pathway, is activated through lysosome rupture and that this activation is necessary for the complete activation of the NLRP3 inflammasome through the oligomerization of an adapter protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We also revealed that the activation of the TAK1-JNK pathway is sustained through Ca2+ ions and that calcium/calmodulin-dependent protein kinase type II functions upstream of the TAK1-JNK pathway and specifically regulates lysosome rupture-induced NLRP3 inflammasome activation. These data suggest a novel role for the TAK1-JNK pathway as a critical regulator of NLRP3 inflammasome activation. 相似文献
12.
Macrophages mediate flagellin induced inflammasome activation and host defense in zebrafish 下载免费PDF全文
William J.B. Vincent Christina M. Freisinger Pui‐ying Lam Anna Huttenlocher John‐Demian Sauer 《Cellular microbiology》2016,18(4):591-604
The inflammasome is an innate immune complex whose rapid inflammatory outputs play a critical role in controlling infection; however, the host cells that mediate inflammasome responses in vivo are not well defined. Using zebrafish larvae, we examined the cellular immune responses to inflammasome activation during infection. We compared the host responses with two Listeria monocytogenes strains: wild type and Lm‐pyro, a strain engineered to activate the inflammasome via ectopic expression of flagellin. Infection with Lm‐pyro led to activation of the inflammasome, macrophage pyroptosis and ultimately attenuation of virulence. Depletion of caspase A, the zebrafish caspase‐1 homolog, restored Lm‐pyro virulence. Inflammasome activation specifically recruited macrophages to infection sites, whereas neutrophils were equally recruited to wild type and Lm‐pyro infections. Similar to caspase A depletion, macrophage deficiency rescued Lm‐pyro virulence to wild‐type levels, while defective neutrophils had no specific effect. Neutrophils were, however, important for general clearance of L. monocytogenes, as both wild type and Lm‐pyro were more virulent in larvae with defective neutrophils. This study characterizes a novel model for inflammasome studies in an intact host, establishes the importance of macrophages during inflammasome responses and adds importance to the role of neutrophils in controlling L. monocytogenes infections. 相似文献
13.
The Arabidopsis CERK1‐associated kinase PBL27 connects chitin perception to MAPK activation 下载免费PDF全文
Tomomi Shirakawa Kazuya Ishikawa Masayuki Fujiwara Mari Narusaka Yoshihiro Narusaka Kazuya Ichimura Yuka Kobayashi Hidenori Matsui Yuko Nomura Mika Nomoto Yasuomi Tada Yoichiro Fukao Tamo Fukamizo Kenichi Tsuda Ken Shirasu Naoto Shibuya Tsutomu Kawasaki 《The EMBO journal》2016,35(22):2468-2483
Perception of microbe‐associated molecular patterns by host cell surface pattern recognition receptors (PRRs) triggers the intracellular activation of mitogen‐activated protein kinase (MAPK) cascades. However, it is not known how PRRs transmit immune signals to MAPK cascades in plants. Here, we identify a complete phospho‐signaling transduction pathway from PRR‐mediated pathogen recognition to MAPK activation in plants. We found that the receptor‐like cytoplasmic kinase PBL27 connects the chitin receptor complex CERK1‐LYK5 and a MAPK cascade. PBL27 interacts with both CERK1 and the MAPK kinase kinase MAPKKK5 at the plasma membrane. Knockout mutants of MAPKKK5 compromise chitin‐induced MAPK activation and disease resistance to Alternaria brassicicola. PBL27 phosphorylates MAPKKK5 in vitro, which is enhanced by phosphorylation of PBL27 by CERK1. The chitin perception induces disassociation between PBL27 and MAPKKK5 in vivo. Furthermore, genetic evidence suggests that phosphorylation of MAPKKK5 by PBL27 is essential for chitin‐induced MAPK activation in plants. These data indicate that PBL27 is the MAPKKK kinase that provides the missing link between the cell surface chitin receptor and the intracellular MAPK cascade in plants. 相似文献
14.
Elma Lima Leite Arthur Gautron Martine Deplanche Aurlie Nicolas Jordane Ossemond Minh‐Thu Nguyen Fillipe L. R. do Carmo David Gilot Vasco Azevedo Friedrich Gtz Yves Le Loir Michael Otto Nadia Berkova 《Cellular microbiology》2020,22(8)
Staphylococcus aureus, a versatile Gram‐positive bacterium, is the main cause of bone and joint infections (BJI), which are prone to recurrence. The inflammasome is an immune signaling platform that assembles after pathogen recognition. It activates proteases, most notably caspase‐1 that proteolytically matures and promotes the secretion of mature IL‐1β and IL‐18. The role of inflammasomes and caspase‐1 in the secretion of mature IL‐1β and in the defence of S. aureus‐infected osteoblasts has not yet been fully investigated. We show here that S. aureus‐infected osteoblast‐like MG‐63 but not caspase‐1 knock‐out CASP1 ?/?MG‐63 cells, which were generated using CRISPR‐Cas9 technology, activate the inflammasome as monitored by the release of mature IL‐1β. The effect was strain‐dependent. The use of S. aureus deletion and complemented phenole soluble modulins (PSMs) mutants demonstrated a key role of PSMs in inflammasomes‐related IL‐1β production. Furthermore, we found that the lack of caspase‐1 in CASP1 ?/?MG‐63 cells impairs their defense functions, as bacterial clearance was drastically decreased in CASP1 ?/? MG‐63 compared to wild‐type cells. Our results demonstrate that osteoblast‐like MG‐63 cells play an important role in the immune response against S. aureus infection through inflammasomes activation and establish a crucial role of caspase‐1 in bacterial clearance. 相似文献
15.
Lee HM Yuk JM Kim KH Jang J Kang G Park JB Son JW Jo EK 《Immunology and cell biology》2012,90(6):601-610
Numerous atypical mycobacteria, including Mycobacterium abscessus (Mabc), cause nontuberculous mycobacterial infections, which present a serious public health threat. Inflammasome activation is involved in host defense and the pathogenesis of autoimmune diseases. However, inflammasome activation has not been widely characterized in human macrophages infected with atypical mycobacteria. Here, we demonstrate that Mabc robustly activates the nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via dectin-1/Syk-dependent signaling and the cytoplasmic scaffold protein p62/SQSTM1 (p62) in human macrophages. Both dectin-1 and Toll-like receptor 2 (TLR2) were required for Mabc-induced mRNA expression of pro-interleukin (IL)-1β, cathelicidin human cationic antimicrobial protein-18/LL-37 and β-defensin 4 (DEFB4). Dectin-1-dependent Syk signaling, but not that of MyD88, led to the activation of caspase-1 and secretion of IL-1β through the activation of an NLRP3/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasome. Additionally, potassium efflux was required for Mabc-induced NLRP3/ASC inflammasome activation. Furthermore, Mabc-induced p62 expression was critically involved in NLRP3 inflammasome activation in human macrophages. Finally, NLRP3/ASC was critical for the inflammasome in antimicrobial responses to Mabc infection. Taken together, these data demonstrate the induction mechanism of the NLRP3/ASC inflammasome and its role in innate immunity to Mabc infection. 相似文献
16.
17.
H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose 下载免费PDF全文
Xiaohui Zhang Yu Fu Hui Li Li Shen Qing Chang Liya Pan Siting Hong Xinhua Yin 《Journal of cellular and molecular medicine》2018,22(3):1816-1825
Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy. 相似文献
18.
Ivan Tattoli Andrzej Grajkowski Assaf Levi Beverly H Koller Irving C Allen Serge L Beaucage Katherine A Fitzgerald Jenny P ‐Y Ting John C Cambier Stephen E Girardin Christian Schindler 《EMBO reports》2013,14(10):900-906
The cyclic dinucleotides 3'‐5'diadenylate (c‐diAMP) and 3'‐5' diguanylate (c‐diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN‐Is) through the c‐diGMP‐binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL‐1β through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c‐diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen‐associated molecular patterns associated with intracellular infections. 相似文献
19.
NLRP11 disrupts MAVS signalosome to inhibit type I interferon signaling and virus‐induced apoptosis 下载免费PDF全文
Chenglei Wu Shouheng Jin Weihong Xie Wei Jiang Rongbin Zhou Jun Cui 《EMBO reports》2017,18(12):2160-2171
MAVS signalosome plays an important role in RIG‐I‐like receptor (RLR)‐induced antiviral signaling. Upon the recognition of viral RNAs, RLRs activate MAVS, which further recruits TRAF6 and other signaling proteins to initiate type I interferon (IFN) activation. MAVS signalosome also regulates virus‐induced apoptosis to limit viral replication. However, the mechanisms that control the activity of MAVS signalosome are still poorly defined. Here, we report NLRP11, a Nod‐like receptor, is induced by type I IFN and translocates to mitochondria to interact with MAVS upon viral infection. Using MAVS as a platform, NLRP11 degrades TRAF6 to attenuate the production of type I IFNs as well as virus‐induced apoptosis. Our findings reveal the regulatory role of NLRP11 in antiviral immunity by disrupting MAVS signalosome. 相似文献