scholarly journals GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages

2021 ◽  
Author(s):  
Qing Zhang ◽  
Lin-hai Chen ◽  
Hui Yang ◽  
You-chen Fang ◽  
Si-wei Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Mucosal Inflammation ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Inflammatory Stimuli ◽  
Monocytes And Macrophages ◽  
And Function ◽  
Inflammatory Macrophages

AbstractThe putative medium-chain free fatty acid receptor GPR84 is a G protein-coupled receptor primarily expressed in myeloid cells that constitute the innate immune system, including neutrophils, monocytes, and macrophages in the periphery and microglia in the brain. The fact that GPR84 expression in leukocytes is remarkably increased under acute inflammatory stimuli such as lipopolysaccharide (LPS) and TNFα suggests that it may play a role in the development of inflammatory and fibrotic diseases. Here we demonstrate that GPR84 is highly upregulated in inflamed colon tissues of active ulcerative colitis (UC) patients and dextran sulfate sodium (DSS)-induced colitis mice. Infiltrating GPR84+ macrophages are significantly increased in the colonic mucosa of both the UC patients and the mice with colitis. Consistently, GPR84−/− mice are resistant to the development of colitis induced by DSS. GPR84 activation imposes pro-inflammatory properties in colonic macrophages through enhancing NLRP3 inflammasome activation, while the loss of GPR84 prevents the M1 polarization and properties of proinflammatory macrophages. CLH536, a novel GPR84 antagonist discovered by us, suppresses colitis by reducing the polarization and function of pro-inflammatory macrophages. These results define a unique role of GPR84 in innate immune cells and intestinal inflammation, and suggest that GPR84 may serve as a potential drug target for the treatment of UC.

scholarly journals Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Takayuki Komatsu ◽  
Yukie Tanaka ◽  
Yoshinori Kitagawa ◽  
Naoki Koide ◽  
Yoshikazu Naiki ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Innate Immune ◽  
Parainfluenza Virus ◽  
Inflammasome Activation ◽  
V Protein ◽  
Nlrp3 Inflammasome Activation ◽  
Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

scholarly journals Growth differentiation factor 11 ameliorates experimental colitis by inhibiting NLRP3 inflammasome activation

2018 ◽  
Vol 315 (6) ◽  
pp. G909-G920 ◽  
Author(s):  
Lanju Wang ◽  
Yaohui Wang ◽  
Zhenfeng Wang ◽  
Yu Qi ◽  
Beibei Zong ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Inflammasome Activation ◽  
Acute Colitis ◽  
Pyrin Domain ◽  
Differentiation Factor ◽  
Nlrp3 Inflammasome Activation ◽  
Receptor Family

Growth differentiation factor 11 (GDF11) has an anti-inflammatory effect in the mouse model of atherosclerosis and Alzheimer's disease, but how GDF11 regulates intestinal inflammation during ulcerative colitis (UC) is poorly defined. The Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome is closely associated with intestinal inflammation because of its ability to increase IL-1β secretion. Our aim is to determine whether GDF11 has an effect on attenuating experimental colitis in mice. In this study, using a dextran sodium sulfate (DSS)-induced acute colitis mouse model, we reported that GDF11 treatment attenuated loss of body weight, the severity of the disease activity index, shortening of the colon, and histological changes in the colon. GDF11 remarkably suppressed IL-1β secretion and NLRP3 inflammasome activation in colon samples and RAW 264.7 cells, such as the levels of NLRP3 and activated caspase-1. Furthermore, we found that GDF11 inhibited NLRP3 inflammasome activation by downregulating the Toll-like receptor 4/NF-κB p65 pathway and reactive oxygen species production via the typical Smad2/3 pathway. Thus, our research shows that GDF11 alleviates DSS-induced colitis by inhibiting NLRP3 inflammasome activation, providing some basis for its potential use in the treatment of UC. NEW & NOTEWORTHY Here, we identify a new role for growth differentiation factor 11 (GDF11), which ameliorates dextran sodium sulfate-induced acute colitis. Meanwhile, we discover a new phenomenon of GDF11 inhibiting IL-1β secretion and Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome activation. These findings reveal that GDF11 is a new potential candidate for the treatment of ulcerative colitis patients with a hyperactive NLRP3 inflammasome.

scholarly journals NLRP3 Inflammasome in Diabetic Cardiomyopathy and Exercise Intervention

2021 ◽  
Vol 22 (24) ◽  
pp. 13228
Author(s):  
Yi Sun ◽  
Shuzhe Ding
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Nlrp3 Inflammasome ◽  
Exercise Intervention ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Chronic Exercise ◽  
Nlrp3 Inflammasome Activation ◽  
Low Grade Inflammation

Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.

scholarly journals The NLRP3 inflammasome mediates DSS-induced intestinal inflammation in Nod2 knockout mice

2019 ◽  
Vol 25 (2) ◽  
pp. 132-143 ◽  
Author(s):  
Benjamin Umiker ◽  
Hyun-Hee Lee ◽  
Julia Cope ◽  
Nadim J. Ajami ◽  
Jean-Philippe Laine ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
Intestinal Epithelial ◽  
Loss Of Function ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Chronic Disorder ◽  
Molecule Inhibitor ◽  
Pathway Inhibition

Crohn’s disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss of function mutations in the intracellular bacterial sensor NOD2 are major risk factors for the development of CD. In the absence of robust bacterial recognition by NOD2 an inflammatory cascade is initiated through alternative PRRs leading to CD. In the present study, MCC950, a specific small molecule inhibitor of NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced intestinal inflammation in Nod2−/− mice. NLRP3 inflammasome formation was observed at a higher rate in NOD2-deficient small intestinal lamina propria cells after insult by DSS. NLRP3 complex formation led to an increase in IL-1β secretion in both the small intestine and colon of Nod2ko mice. This increase in IL-1β secretion in the intestine was attenuated by MCC950 leading to decreased disease severity in Nod2ko mice. Our work suggests that NLRP3 inflammasome activation may be a key driver of intestinal inflammation in the absence of functional NOD2. NLRP3 pathway inhibition can prevent intestinal inflammation in the absence of robust NOD2 signaling.

Increasing Autophagy ameliorate all-trans-retinal-activated NLRP3 Inflammasome 2 in human THP-1 macrophage cells

2021 ◽  
Author(s):  
Qingqing Xia ◽  
Lvxing Huang ◽  
Hengyi Chen ◽  
Yingying Zhou ◽  
Lingmin Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Innate Immune ◽  
Cell Counting ◽  
Autophagic Flux ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Related Proteins ◽  
Excessive Activation ◽  
Insight Into

Abstract BackgroundProfound inflammation that mediated by innate immune sensors can be observed in retina, and is considered to play an important role in the pathogenesis of all-trans-retinal (atRAL)-caused retinal degeneration. However, the underlying mechanism remains elusive. MethodsCell viability was detected with Cell Counting Kit-8 (CCK-8). The concentration of IL-1β was evaluated using IL-1β ELISA Kits. The levels of autophagy-related proteins were measured by Western blotting. The measurement of autophagic flux was performed with virus vectors packing tandem monomeric mCherry-eGFP-tagged LC3B. ResultsWe focused on studying the effects of atRAL on macrophage cell line THP-1 and determining the underlying signal pathway through pharmacological and genetical manipulation. We first found the maturation and release of IL-1β was regulated by the activation of NLRP3 inflammasome. We secondly found that mitochondria-associated reactive oxygen species (ROS) were involved in the regulation of NLRP3 inflammasome activation and caspase 1 cleavage. Finally, we found that atRAL functionally activated autophagy in THP-1 cells, and atRAL-caused NLRP3 inflammasome activation is suppressed by autophagy. Overall, our results show atRAL simultaneously activates NLRP3 inflammasome and autophagy in THP-1 cells, and increasing autophagy leads to the inhibition of the excessive activation of NLRP3 inflammasome. Our study provides new insight into the pathogenesis of aging related retina degeneration.

scholarly journals Deoxycholic Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Exacerbates DSS-Induced Colitis through Promoting Cathepsin B Release

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Shengnan Zhao ◽  
Zizhen Gong ◽  
Xixi Du ◽  
Chunyan Tian ◽  
Lingyu Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Cathepsin B ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Inflammasome Activation ◽  
High Fat ◽  
Molecular Pattern ◽  
Nlrp3 Inflammasome Activation ◽  
Sphingosine 1 Phosphate

We recently have proved that excessive fecal DCA caused by high-fat diet may serve as an endogenous danger-associated molecular pattern to activate NLRP3 inflammasome and thus contributes to the development of inflammatory bowel disease (IBD). Moreover, the effect of DCA on inflammasome activation is mainly mediated through bile acid receptor sphingosine-1-phosphate receptor 2 (S1PR2); however, the intermediate process remains unclear. Here, we sought to explore the detailed molecular mechanism involved and examine the effect of S1PR2 blockage in a colitis mouse model. In this study, we found that DCA could dose dependently upregulate S1PR2 expression. Meanwhile, DCA-induced NLRP3 inflammasome activation is at least partially achieved through stimulating extracellular regulated protein kinases (ERK) signaling pathway downstream of S1PR2 followed by promoting of lysosomal cathepsin B release. DCA enema significantly aggravated DSS-induced colitis in mice and S1PR2 inhibitor as well as inflammasome inhibition by cathepsin B antagonist substantially reducing the mature IL-1β production and alleviated colonic inflammation superimposed by DCA. Therefore, our findings suggest that S1PR2/ERK1/2/cathepsin B signaling plays a critical role in triggering inflammasome activation by DCA and S1PR2 may represent a new potential therapeutic target for the management of intestinal inflammation in individuals on a high-fat diet.

scholarly journals The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1808 ◽  
Author(s):  
Allison K. Meyers ◽  
Xuewei Zhu
Keyword(s):  
Nlrp3 Inflammasome ◽  
Metabolic Regulation ◽  
Inflammasome Activation ◽  
Immune Effector ◽  
Effector Functions ◽  
Pyrin Domain ◽  
Inflammatory Conditions ◽  
Nlrp3 Inflammasome Activation ◽  
Inflammatory Stimuli ◽  
Pro Inflammatory Cytokines

In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The NLRP3 inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the NLRP3 inflammasome. This review focuses on our current understanding of the metabolic regulation of the NLRP3 inflammasome activation, and the contribution of the NLRP3 inflammasome to inflammaging.

scholarly journals Pretreatment with a Heat-Killed Probiotic Modulates the NLRP3 Inflammasome and Attenuates Colitis-Associated Colorectal Cancer in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 516 ◽  
Author(s):  
I-Che Chung ◽  
Chun-Nan OuYang ◽  
Sheng-Ning Yuan ◽  
Hsin-Chung Lin ◽  
Kuo-Yang Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Inflammasome Activation ◽  
E Coli ◽  
Nlrp3 Inflammasome Activation ◽  
Safe Strategy ◽  
Inflammatory Bowel ◽  
Fecal Content

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according to the reduction of caspase-1 activation and IL-1β maturation. Mechanistically, E. faecalis attenuates the phagocytosis that is required for the full activation of the NLRP3 inflammasome. In in vivo mouse experiments, E. faecalis can ameliorate the severity of intestinal inflammation and thereby protect mice from dextran sodium sulfate (DSS)-induced colitis and the formation of CRC in wild type mice. On the other hand, E. faecalis cannot prevent DSS-induced colitis in NLRP3 knockout mice. Our findings indicate that application of the inactivated probiotic, E. faecalis, may be a useful and safe strategy for attenuation of NLRP3-mediated colitis and inflammation-associated colon carcinogenesis.

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