共查询到20条相似文献,搜索用时 15 毫秒
1.
Dong‐Jae Kim Jong‐Hwan Park Luigi Franchi Steffen Backert Gabriel Núñez 《European journal of immunology》2013,43(10):2650-2658
Helicobacter pylori colonization of the stomach affects about half of the world population and is associated with the development of gastritis, ulcers, and cancer. Polymorphisms in the IL1B gene are linked to an increased risk of H. pylori associated cancer, but the bacterial and host factors that regulate interleukin (IL)‐1β production in response to H. pylori infection remain unknown. Using murine BM‐derived DCs, we show that the bacterial virulence factors cytotoxin‐associated genes pathogenicity island and CagL, but not vacuolating cytotoxin A or CagA, regulate the induction of pro‐IL‐1β and the production of mature IL‐1β in response to H. pylori infection. We further show that the host receptors, Toll‐like receptor 2 (TLR2) and nucleotide‐binding oligomerization domain 2 (NOD2), but not NOD1, are required for induction of pro‐IL‐1β and NOD‐like receptor pyrin domain containing 3 (NLRP3) in H. pylori infected DCs. In contrast, NLRP3 and the adaptor ASC were essential for the activation of caspase‐1, processing of pro‐IL‐1β into IL‐1β, and IL‐1β secretion. Finally, we show that mice deficient in caspase‐1, IL‐1β, and IL‐1 receptor, but not NLRP3, are impaired in the clearance of CagA‐positive H. pylori from the stomach when compared with WT mice. These studies identify bacterial cag pathogenicity island and the cooperative interaction among host innate receptors TLR2, NOD2, and NLRP3 as important regulators of IL‐1β production in H. pylori infected DCs. 相似文献
2.
IL‐1β activation in response to Staphylococcus aureus lung infection requires inflammasome‐dependent and independent mechanisms 下载免费PDF全文
Maintaining balanced levels of IL‐1β is extremely important to avoid host tissue damage during infection. Our goal was to understand the mechanisms behind the reduced pathology and decreased bacterial burdens in Ifnlr1?/? mice during lung infection with Staphylococcus aureus. Intranasal infection of Ifnlr1?/? mice with S. aureus led to significantly improved bacterial clearance, survival and decrease of proinflammatory cytokines in the airway including IL‐1β. Ifnlr1?/? mice treated with recombinant IL‐1β displayed increased bacterial burdens in the airway and lung. IL‐1β levels in neutrophils from Ifnlr1?/? infected mice lungs were decreased when compared to neutrophils from WT mice. Mice lacking NLRP3 and caspase‐1 had reduced IL‐1β levels 4 h after infection, due to reductions or absence of active caspase‐1 respectively, but levels at 24 h were comparable to WT infected mice. Ifnlr1?/? infected mice had decreases in both active caspase‐1 and neutrophil elastase indicating an important role for the neutrophil serine protease in IL‐1β processing. By inhibiting neutrophil elastase, we were able to decrease IL‐1β levels by 39% in Nlrp3?/? infected mice when compared to WT mice. These results highlight the crucial role of both proteases in IL‐1β processing, via inflammasome‐dependent and ‐independent mechanisms. 相似文献
3.
《Immunology》2017,151(2):154-166
Sporotrichosis is a mycosis caused by fungi from the Sporothrix schenckii species complex, whose prototypical member is Sporothrix schenckii sensu stricto. Pattern recognition receptors (PRRs) recognize and respond to pathogen‐associated molecular patterns (PAMPs) and shape the following adaptive immune response. A family of PRRs most frequently associated with fungal recognition is the nucleotide‐binding oligomerization domain‐like receptor (NLR). After PAMP recognition, NLR family pyrin domain‐containing 3 (NLRP3) binds to apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC) and caspase‐1 to form the NLRP3 inflammasome. When activated, this complex promotes the maturation of the pro‐inflammatory cytokines interleukin‐1β (IL‐1β) and IL‐18 and cell death through pyroptosis. In this study, we aimed to evaluate the importance of the NLRP3 inflammasome in the outcome of S. schenckii infection using the following three different knockout (KO) mice: NLRP3−/−, ASC−/− and caspase‐1−/−. All KO mice were more susceptible to infection than the wild‐type, suggesting that NLRP3‐triggered responses contribute to host protection during S. schenckii infection. Furthermore, the NLRP3 inflammasome appeared to be critical for the ex vivo release of IL‐1β, IL‐18 and IL‐17 but not interferon‐γ. Additionally, a role for the inflammasome in shaping the adaptive immune response was suggested by the lower frequencies of type 17 helper T (Th17) cells and Th1/Th17 but not Th1 cells in S. schenckii‐infected KO mice. Overall, our results indicate that the NLRP3 inflammasome links the innate recognition of S. schenckii to the adaptive immune response, so contributing to protection against this infection. 相似文献
4.
Effect of enterohaemorrhagic Escherichia coli O157:H7‐specific enterohaemolysin on interleukin‐1β production differs between human and mouse macrophages due to the different sensitivity of NLRP3 activation 下载免费PDF全文
Yu‐Li Cheng Li‐qiong Song Yuan‐Ming Huang Yan‐Wen Xiong Xiao‐Ai Zhang Hui Sun Xin‐Ping Zhu Guang‐Xun Meng Jian‐Guo Xu Zhi‐Hong Ren 《Immunology》2015,145(2):258-267
Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection in humans can cause acute haemorrhagic colitis and severe haemolytic uraemic syndrome. The role of enterohaemolysin (Ehx) in the pathogenesis of O157:H7‐mediated disease in humans remains undefined. Recent studies have revealed the importance of the inflammatory response in O157:H7 pathogenesis in humans. We previously reported that Ehx markedly induced interleukin‐1β (IL‐1β) production in human macrophages. Here, we investigated the disparity in Ehx‐induced IL‐1β production between human and mouse macrophages and explored the underlying mechanism regarding the activation of NOD‐like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes. In contrast to the effects on human differentiated THP‐1 cells and peripheral blood mononuclear cells, Ehx exerted no effect on IL‐1β production in mouse macrophages and splenocytes because of a disparity in pro‐IL‐1β cleavage into mature IL‐1β upon caspase‐1 activation. Additionally, Ehx significantly contributed to O157:H7‐induced ATP release from THP‐1 cells, which was not detected in mouse macrophages. Confocal microscopy demonstrated that Ehx was a key inducer of cathepsin B release in THP‐1 cells but not in mouse IC‐21 cells upon O157:H7 challenge. Inhibitor experiments indicated that O157:H7‐induced IL‐1β production was largely dependent upon caspase‐1 activation and partially dependent upon ATP signalling and cathepsin B release, which were both involved in NLRP3 activation. Moreover, inhibition of K+ efflux drastically diminished O157:H7‐induced IL‐1β production and cytotoxicity. The findings in this study may shed light on whether and how the Ehx contributes to the development of haemolytic uraemic syndrome in human O157:H7 infection. 相似文献
5.
Follistatin‐like protein 1 enhances NLRP3 inflammasome‐mediated IL‐1β secretion from monocytes and macrophages 下载免费PDF全文
Yury Chaly Yu Fu Anthony Marinov Bruce Hostager Wei Yan Brian Campfield John A. Kellum Daniel Bushnell Yudong Wang Jerry Vockley Raphael Hirsch 《European journal of immunology》2014,44(5):1467-1479
6.
The Nlrp3 inflammasome,IL‐1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice 下载免费PDF全文
Melanie Charmoy Benjamin P. Hurrell Audrey Romano Sang Hun Lee Flavia Ribeiro‐Gomes Nicolas Riteau Katrin Mayer‐Barber Fabienne Tacchini‐Cottier David L. Sacks 《European journal of immunology》2016,46(4):897-911
Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL‐1β mRNA and IL‐1β‐producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain, or caspase‐1/11, or lacking IL‐1β or IL‐1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen‐specific Th1 response. The possibility that IL‐1β might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL‐1β by LmSd‐infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase‐1. These data reveal that Nlrp3 inflammasome‐dependent IL‐1β, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice. 相似文献
7.
Potassium efflux fires the canon: Potassium efflux as a common trigger for canonical and noncanonical NLRP3 pathways 下载免费PDF全文
Murine caspase‐11 and its human orthologues, caspase‐4 and caspase‐5, activate an inflammatory response following cytoplasmic recognition of cell wall constituents from Gram‐negative bacteria, such as LPS. This inflammatory response involves pyroptotic cell death and the concomitant release of IL‐1α, as well as the production of IL‐1β and IL‐18 through the noncanonical NLR family, pyrin domain containing 3 (NLRP3) pathway. This commentary discusses three papers in this issue of the European Journal of Immunology that advance our understanding of the roles of caspase‐11, ‐4, and ‐5 in the noncanonical pathway. By utilizing the new gene editing technique, clustered regularly interspaced short palindromic repeats (CRISPR), as well as sensitive cell imaging techniques, these papers establish that cytoplasmic LPS‐dependent IL‐1β production requires the NLRP3 inflammasome and that its activation is dependent on K+ efflux, whereas IL‐1α release and pyroptotic cell death pathways are NLRP3‐independent. These findings expand on previous research implicating K+ efflux as the principal trigger for NLRP3 activation and suggest that canonical and noncanonical NLRP3 pathways are not as dissimilar as first thought. 相似文献
8.
Andrea J. McCoy Yukiko Koizumi Claudia Toma Naomi Higa Vishva Dixit Shun'ichiro Taniguchi Jürg Tschopp Toshihiko Suzuki 《European journal of immunology》2010,40(10):2797-2803
Aeromonas hydrophila is a Gram‐negative pathogen that causes serious infectious disease in humans. A. hydrophila induces apoptosis in infected macrophages, but the host proinflammatory responses triggered by macrophage death are largely unknown. Here, we demonstrate that the infection of mouse macrophages with A. hydrophila triggers the activation of caspase‐1 and release of IL‐1β. Caspase‐1 activation was abrogated in macrophages deficient in Nod‐like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), but not NLR family, CARD domain containing 4 (NLRC4). The activation of the NLRP3 inflammasome was mediated by three cytotoxins (aerolysin, hemolysin and multifunctional repeat‐in‐toxin) produced by A. hydrophila. Our results indicated that the NLRP3 inflammasome senses A. hydrophila infection through the action of bacterial cytotoxins. 相似文献
9.
NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase‐4 and caspase‐5 下载免费PDF全文
Paul J. Baker Dave Boucher Damien Bierschenk Christina Tebartz Paul G. Whitney Damian B. D'Silva Maria C. Tanzer Mercedes Monteleone Avril A. B. Robertson Matthew A. Cooper Silvia Alvarez‐Diaz Marco J. Herold Sammy Bedoui Kate Schroder Seth L. Masters 《European journal of immunology》2015,45(10):2918-2926
Humans encode two inflammatory caspases that detect cytoplasmic LPS, caspase‐4 and caspase‐5. When activated, these trigger pyroptotic cell death and caspase‐1‐dependent IL‐1β production; however the mechanism underlying this process is not yet confirmed. We now show that a specific NLRP3 inhibitor, MCC950, prevents caspase‐4/5‐dependent IL‐1β production elicited by transfected LPS. Given that both caspase‐4 and caspase‐5 can detect cytoplasmic LPS, it is possible that these proteins exhibit some degree of redundancy. Therefore, we generated human monocytic cell lines in which caspase‐4 and caspase‐5 were genetically deleted either individually or together. We found that the deletion of caspase‐4 suppressed cell death and IL‐1β production following transfection of LPS into the cytoplasm, or in response to infection with Salmonella typhimurium. Although deletion of caspase‐5 did not confer protection against transfected LPS, cell death and IL‐1β production were reduced after infection with Salmonella. Furthermore, double deletion of caspase‐4 and caspase‐5 had a synergistic effect in the context of Salmonella infection. Our results identify the NLRP3 inflammasome as the specific platform for IL‐1β maturation, downstream of cytoplasmic LPS detection by caspase‐4/5. We also show that both caspase‐4 and caspase‐5 are functionally important for appropriate responses to intracellular Gram‐negative bacteria. 相似文献
10.
Donatella Pietrella Neelam Pandey Elena Gabrielli Eva Pericolini Stefano Perito Lydia Kasper Francesco Bistoni Antonio Cassone Bernhard Hube Anna Vecchiarelli 《European journal of immunology》2013,43(3):679-692
In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL‐1β, TNF‐α, and IL‐6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL‐1β and IL‐18 production through inflammasome activation. This occurs via NLRP3 and caspase‐1 activation, which cleaves pro‐IL‐1β into secreted bioactive IL‐1β, a cytokine that was induced by Saps in monocytes, in monocyte‐derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL‐1β. Inflammasome activation required Sap internalization via a clathrin‐dependent mechanism, intracellular induction of K+ efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS‐ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity. 相似文献
11.
G. Fantuzzi 《Acta physiologica (Oxford, England)》2001,173(1):5-9
The study of cytokine‐deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)‐1 system is reviewed. Results obtained by studying mice deficient for IL‐1α, IL‐1β, IL‐1 receptor antagonist, IL‐1 receptor type I, IL‐1 receptor accessory protein, IL‐1 receptor‐associated kinase, and the IL‐1β‐converting enzyme caspase‐1 are summarized. Because some of the components of the IL‐1 system are shared with IL‐18, similarities between IL‐1β and IL‐18 are also discussed. 相似文献
12.
IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils 下载免费PDF全文
Ji Hyung Kim Sae Jin Oh Sehee Ahn Doo Hyun Chung 《European journal of immunology》2014,44(7):2025-2035
A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT‐cell‐deficient mice of C57BL/6 background during cecal ligation and puncture‐induced sepsis. The levels of C5a, IFN‐γ, and IL‐10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d?/? mice, while the mortality rate was lower in CD1d?/? mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d?/? mice. As assessed by intracellular staining, NKT cells expressed IFN‐γ, while neutrophils expressed IL‐10. Upon coculture, IL‐10‐deficient NKT cells enhanced IL‐10 production by WT, but not IFN‐γR‐deficient, neutrophils. Meanwhile, CD1d?/? mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL‐10 administration into CD1d?/? mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN‐γ‐deficient, NKT cells into CD1d?/? mice suppressed CD55 expression on neutrophils, but increased IL‐10 and C5a levels. Taken together, IFN‐γ‐producing NKT cells enhance C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis. 相似文献
13.
14.
Impaired NLRP3 inflammasome activity during fetal development regulates IL‐1β production in human monocytes 下载免费PDF全文
Ashish A. Sharma Roger Jen Bernard Kan Abhinav Sharma Elizabeth Marchant Anthony Tang Izabelle Gadawski Christof Senger Amanda Skoll Stuart E. Turvey Laura M. Sly Hélène C.F. Côté Pascal M. Lavoie 《European journal of immunology》2015,45(1):238-249
Interleukin‐1β (IL‐1β) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll‐like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16pos monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro‐IL‐1β precursor protein upon LPS stimulation. In contrast, high levels of pro‐IL‐1β are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL‐1β. The lack of secreted IL‐1β in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase‐1 activity before 29 weeks of gestation, whereas expression of the apoptosis‐associated speck‐like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP‐induced caspase‐1 activity in cord blood monocytes. Lastly, secretion of IL‐1β in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL‐1β responses early in gestation, in part due to a downregulation of TLR‐mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus. 相似文献
15.
Anna Solini Stefano Menini Chiara Rossi Carlo Ricci Eleonora Santini Claudia Blasetti Fantauzzi Carla Iacobini Giuseppe Pugliese 《The Journal of pathology》2013,231(3):342-353
Renal disease associated with type 2 diabetes and the metabolic syndrome is characterized by a distinct inflammatory phenotype. The purinergic 2X7 receptor (P2X7R) and the nucleotide‐binding and oligomerization domain‐like receptor containing a pyrin domain 3 (NLRP3) inflammasome have been separately shown to play a role in two models of non‐metabolic chronic kidney disease. Moreover, the NLRP3 inflammasome has been implicated in chronic low‐grade sterile inflammation characterizing metabolic disorders, though the mechanism(s) involved in inflammasome activation under these conditions are still unknown. We investigated the role of P2X7R (through activation of the NLRP3 inflammasome) in renal inflammation and injury induced by a high‐fat diet, an established model of the metabolic syndrome. On a high‐fat diet, mice lacking P2X7R developed attenuated renal functional and structural alterations as well as reduced inflammation, fibrosis, and oxidative/carbonyl stress, as compared with wild‐type animals, in the absence of significant differences in metabolic parameters. This was associated with blunted up‐regulation of the NLRP3 inflammasome components NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), pro‐caspase 1, pro‐interleukin (IL)‐1β, and pro‐IL‐18, as well as reduced inflammasome activation, as evidenced by decreased formation of mature caspase 1, whereas mature IL‐1β and IL‐18 were not detected. Up‐regulated expression of NLRP3 and pro‐caspase 1, post‐translational processing of pro‐caspase‐1, and release of IL‐18 in response to lipopolysaccharide + 2′(3′)‐O‐(4‐benzoylbenzoyl)ATP were attenuated by P2X7R silencing in cultured mouse podocytes. Protein and mRNA expression of P2X7R, NLRP3, and ASC were also increased in kidneys from subjects with type 2 diabetes and the metabolic syndrome, showing histologically documented renal disease. These data provide evidence of a major role for the purinergic system, at least in part through activation of the NLRP3 inflammasome, in the process driving ‘metabolic’ renal inflammation and injury and identify P2X7R and NLRP3 as novel therapeutic targets. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
16.
Hartmann Raifer Azita J. Mahiny Nadine Bollig Franziska Petermann Anne Hellhund Kerstin Kellner Anna Guralnik Katharina Reinhard Evita Bothur Magdalena Huber Stefan Bauer Max Löhning Elina A. Kiss Stephanie C. Ganal Andreas Diefenbach Thomas Korn Michael Lohoff 《European journal of immunology》2012,42(12):3189-3201
17.
Priscila Carneiro Campos Marco Túlio Ribeiro Gomes Fbio Antnio Vitarelli Marinho Erika Sousa Guimares Mariza Gabriela Faleiro de Moura Lodi Cruz Sergio Costa Oliveira 《European journal of immunology》2019,49(7):1023-1037
NLRP3 inflammasome is a protein complex crucial to caspase‐1 activation and IL‐1β and IL‐18 maturation. This receptor participates in innate immune responses to different pathogens, including the bacteria of genus Brucella. Our group recently demonstrated that Brucella abortus‐induced IL‐1β secretion involves NLRP3 inflammasome and it is partially dependent on mitochondrial ROS production. However, other factors could be involved, such as P2X7‐dependent potassium efflux, membrane destabilization, and cathepsin release. Moreover, there is increasing evidence that nitric oxide acts as a modulator of NLRP3 inflammasome. The aim of this study was to unravel the mechanism of NLRP3 inflammasome activation induced by B. abortus, as well as the involvement of bacterial nitric oxide (NO) as a modulator of this inflammasome pathway. We demonstrated that NO produced by B. abortus can be used by the bacteria to modulate IL‐1β secretion in infected murine macrophages. Additionally, our results suggest that B. abortus‐induced IL‐1β secretion depends on a P2X7‐independent potassium efflux, lysosomal acidification, cathepsin release, mechanisms clearly associated to NLRP3 inflammasome. In summary, our results help to elucidate the molecular mechanisms of NLRP3 activation and regulation during an intracellular bacterial infection. 相似文献
18.
Recognition of microbe‐associated molecular patterns or endogenous danger signals by a subset of cytosolic PRRs results in the assembly of multiprotein signaling complexes, the so‐called inflammasomes. Canonical inflammasomes are assembled by NOD‐like receptor (NLR) or PYHIN family members and activate caspase‐1, which promotes the induction of pyroptosis and the release of mature interleukin‐1β/‐18. Recently, a noncanonical inflammasome pathway was discovered that results in caspase‐11 activation in response to bacterial lipopolysaccharide (LPS) in the cytosol. Interestingly, caspase‐11 induces pyroptosis by itself, but requires NLRP3, the inflammasome adapter ASC, and caspase‐1 to promote cytokine secretion. Here, we have studied the mechanism by which caspase‐11 controls IL‐1β secretion. Investigating NLRP3/ASC complex formation, we find that caspase‐11 functions upstream of a canonical NLRP3 inflammasome. The activation of NLRP3 by caspase‐11 during LPS transfection is a cell‐intrinsic process and is independent of the release of danger signals. Furthermore, we show that active caspase‐11 leads to a drop of intracellular potassium levels, which is necessary to activate NLRP3. Our study, therefore, sheds new light on the mechanism of noncanonical inflammasome signaling. 相似文献
19.
《Mucosal immunology》2018,11(1):257-272
The opportunistic Gram-negative bacterium Acinetobacter baumannii (AB) is a leading cause of life-threatening nosocomial pneumonia. Outbreaks of multidrug resistant (MDR)-AB belonging to international clones (ICs) I and II with limited treatment options are major global health threats. However, the pathogenesis mechanisms of various AB clonal groups are understudied. Although inflammation-associated interleukin-1β (IL-1β) levels and IL-1 receptor antagonist polymorphisms were previously implicated in MDR-AB-related pneumonia in patients, whether inflammasomes has any role in the host defense and/or pathogenesis of clinically relevant A. baumannii infection is unknown. Using a sublethal mouse pneumonia model, we demonstrate that an extensively drug-resistant clinical isolate (ICII) of A. baumannii exhibits reduced/delayed early pulmonary neutrophil recruitment, higher lung persistence, and, most importantly, elicits enhanced IL-1β/IL-18 production and lung damage through NLRP3 inflammasome, in comparison with A. baumannii-type strain. A. baumannii infection-induced IL-1β/IL-18 production is entirely dependent on NLRP3-ASC-caspase-1/caspase-11 pathway. Using Nlrp3−/− mice infection models, we further show that while NLRP3 inflammasome pathway contributes to host defense against A. baumannii clinical isolate, it is dispensable for protection against A. baumannii-type strain. Our study reveals a novel differential role for NLRP3 inflammasome pathway in the immunity against clinically relevant A. baumannii infections, and highlights inflammasome pathway as a potential immunomodulatory target. 相似文献
20.
Vladislav Volarevic Bojana Simovic Markovic Sanja Bojic Maja Stojanovic Ulf Nilsson Hakon Leffler Gurdyal S. Besra Nebojsa Arsenijevic Verica Paunovic Vladimir Trajkovic Miodrag L. Lukic 《European journal of immunology》2015,45(2):531-543
Galectin‐3 (Gal‐3), an endogenous lectin, exhibits pro‐ and anti‐inflammatory effects in various disease conditions. In order to explore the role of Gal‐3 in NKT‐cell‐dependent pathology, we induced hepatitis in C57BL/6 WT and Gal‐3‐deficient mice by using specific ligand for NKT cells: α‐galactosylceramide, glycolipid Ag presented by CD1d. The injection of α‐galactosylceramide significantly enhanced expression of Gal‐3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal‐3 (induced by Gal‐3‐inhibitor TD139) abrogated the susceptibility to NKT‐cell‐dependent hepatitis. Blood levels of pro‐inflammatory cytokines (TNF‐α, IFN‐γ, IL‐12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal‐3 alleviated influx of inflammatory CD11c+CD11b+ DCs in the liver and favored tolerogenic phenotype and IL‐10 production of liver NKT and DCs. Deletion of Gal‐3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro‐inflammatory cytokines in vitro. Gal‐3‐deficient DCs failed to optimally stimulate production of pro‐inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal‐3 regulates the capacity of DCs to support NKT‐cell‐mediated liver injury, playing an important pro‐inflammatory role in acute liver injury. 相似文献