scholarly journals Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

2017 ◽  
Vol 41 (1) ◽  
pp. 193-204 ◽  
Author(s):  
Michael Bording-Jorgensen ◽  
Misagh Alipour ◽  
Eytan Wine ◽  
Ghazal Danesh
Keyword(s):  
Ros Generation ◽  
Inflammasome Activation ◽  
Bacterial Survival ◽  
Citrobacter Rodentium ◽  
Bacterial Killing ◽  
Pyrin Domain ◽  
Gentamicin Protection Assay ◽  
Macrophage Killing ◽  
Inflammasome Activity ◽  
Receptor Family

Background: Nod-like receptor family, pyrin domain containing 3 (NLRP3) is an important cytosolic sensor of cellular stress and infection. Once activated, NLRP3 forms a multiprotein complex (inflammasome) that triggers the maturation and secretion of interleukin (IL)-1β and IL-18. We aimed to define the consequences of NLRP3 induction, utilizing exogenous adenosine triphosphate (ATP) as an inflammasome activator, to determine if inflammasome activation increases macrophage killing of Citrobacter rodentium and define mechanisms. Methods: Bacterial survival was measured using a gentamicin protection assay. Inflammasome activation or inhibition in mouse J774A.1 macrophages were assessed by measuring IL-1β; cytokines and reactive oxygen species (ROS) were measured by ELISA and DCFDA, respectively. Results: Activation of the inflammasome increased bacterial killing by macrophages and its inhibition attenuated this effect with no impact on phagocytosis or cell death. Furthermore, inflammasome activation suppressed pro-inflammatory cytokines during infection, possibly due to more effective bacterial killing. While the infection increased ROS production, this effect was reduced by inflammasome inhibitors, indicating that ROS is inflammasome-dependent. ROS inhibitors increased bacterial survival in the presence of ATP, suggesting that inflammasome-induced bacterial killing is mediated, at least in part, by ROS activity. Conclusion: Improving inflammasome activity during infection may increase bacterial clearance by macrophages and reduce subsequent microbe-induced inflammation.

scholarly journals LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients.

2021 ◽  
Author(s):  
Giuseppe Bombaci ◽  
Mayuresh A Sarangdhar ◽  
Nicola Andina ◽  
Aubry Tardivel ◽  
Eric Chi-Wang Yu ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Neutrophil Infiltration ◽  
Inflammasome Activation ◽  
Ribonuclease Inhibitor ◽  
Protein Levels ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
Lrr Protein ◽  
Receptor Family

Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated inflammation. Although inflammation is protective, uncontrolled excessive inflammation can cause inflammatory diseases and is also detrimental in COVID-19 infection. However, the underlying mechanisms that control inflammasome activation are incompletely understood. Here we report that the leucine rich repeat (LRR) protein Ribonuclease inhibitor (RNH1), which shares homology with LRRs of NOD-like receptor family pyrin domain (PYD)-containing (NLRP) proteins, attenuates inflammasome activation. Mechanistically, RNH1 decreased pro-IL1b expression and induced proteasome-mediated caspase-1 degradation. Corroborating this, mouse models of monosodium urate (MSU)-induced peritonitis and LPS-induced endotoxemia, which are dependent on caspase-1, respectively showed increased neutrophil infiltration and lethality in Rnh1-/- mice compared to WT mice. Further, RNH1 protein levels were negatively correlated with inflammation and disease severity in hospitalized COVID-19 patients. We propose that RNH1 is a new inflammasome regulator with relevance to COVID-19 severity.

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 Is Involved in Calcium-Sensing Receptor-Induced Aortic Remodeling in SHRs

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Zhang ◽  
Siting Hong ◽  
Shuhan Qi ◽  
Wenxiu Liu ◽  
Xiaohui Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Activation Mechanism ◽  
Inflammasome Activation ◽  
Calcium Sensing Receptor ◽  
Pyrin Domain ◽  
Calcium Sensing ◽  
Nlrp3 Inflammasome Activation ◽  
Nucleotide Oligomerization ◽  
Aortic Remodeling ◽  
Receptor Family

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.

Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation

Pharmacology ◽  
2018 ◽  
Vol 101 (5-6) ◽  
pp. 236-245 ◽  
Author(s):  
Shiro Nakamura ◽  
Toshio Watanabe ◽  
Tetsuya Tanigawa ◽  
Sunao Shimada ◽  
Yuji Nadatani ◽  
...  
Keyword(s):  
Small Intestine ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Intestinal Damage ◽  
Protein Levels ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Small Intestinal ◽  
Receptor Family

Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1β in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1β in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1β. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1β. NLRP3–/– and caspase-1–/– mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3–/– and caspase-1–/– mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation.

scholarly journals A190 ATP-INDUCED INFLAMMASOME ACTIVATION GENERATES MITOCHONDRIAL ROS PRODUCTION IN MACROPHAGES

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 206-207
Author(s):  
M Bording-Jorgensen ◽  
H Armstrong ◽  
E Wine
Keyword(s):  
Nlrp3 Inflammasome ◽  
Extracellular Atp ◽  
Inflammasome Activation ◽  
Ros Production ◽  
Bacterial Survival ◽  
Bacterial Killing ◽  
Beneficial Effects ◽  
Inflammatory Conditions ◽  
Mitochondrial Ros

Abstract Background The etiology of Inflammatory Bowel Diseases is unknown; however, a dysfunctional immune response has been well characterized. The role of the NLRP3 inflammasome in IBD is controversial with both beneficial and detrimental results. This pathway is required for the secretion of the proinflammatory cytokine IL-1β. Extracellular ATP is a well characterized inflammasome activator, which we have previously shown can increase the ability of J774A.1 macrophages to clear the mouse pathogen Citrobacter rodentium in an in vitro environment through the generation of reactive oxygen species (ROS). Aims Our objectives were to determine: 1) if extracellular ATP was inducing mitochondrial stress, causing the production of ROS, leading to microbial death; and 2) what effects these activated macropahges have on naïve macrophages. Methods Murine macrophage J774A.1 cells were infected with C. rodentium; extracellular ATP was added as an inflammasome activator and YVAD as an inhibitor. Lysotracker red and MitoSOX were used to determine cellular location of bacteria and quantify mitochondrial ROS, respectively. Secreted cytokines were measured using ELISA and a proteome profiler, ROS was measured using DCFDA, Gasdermin D and Caspase 11 activities were determined by Western Blot. Supernatants taken from infected macrophages were filtered and then added to naïve macrophages during infection with C. rodentium. Results Activation of mitochondrial ROS by ATP was found to be independent of infection. Secreted cytokines sICAM-1, MIP-1α, and MCP-2 were all increased by ATP but not inhibited by YVAD. Cleavage of Gasdermin D was increased with the addition of ATP but not inhibited by YVAD whereas Caspase 11 was unchanged between treatments. Supernatants from ATP-induced macrophages were able to induce IL-1β secretion in naïve macrophages and increase bacterial killing. Conclusions Mitochondrial ROS production in response to extracellular ATP may be involved in the decrease of bacterial survival. ATP induces the secretion of cytokines, chemokines, and other factors that affect newly infected macrophages. Gasdermin D cleavage, independent of caspase 11, suggests that a noncannonical pathway is activated; this may explain the lack of pyroptotic cells in our study. In addition, we have shown that these macrophages are able to illicit the same behavior in naive macrophages, suggesting that a corrected dysfunctional pathway in macrophages can have beneficial effects downstream. Understanding how the NLRP3 inflammasome is activated and what the downstream pathways are may lead to potential therapies for inflammatory conditions, including IBD. Funding Agencies CCC, CIHR

scholarly journals VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sung Kyun Lee ◽  
Ye Seon Kim ◽  
Geon Ho Bae ◽  
Ha Young Lee ◽  
Yoe-Sik Bae
Keyword(s):  
Lung Inflammation ◽  
Cecal Ligation ◽  
Selective Inhibitor ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Mitochondrial Ros ◽  
Phospholipase D1 ◽  
Inflammasome Activity ◽  
Nlrp3 Expression

Abstract The inflammasome is a specialized multiprotein oligomer that regulates IL-1β production. Although regulation of the inflammasome is related to crucial inflammatory disorders such as sepsis, pharmacological inhibitors that effectively inhibit inflammasome activity are limited. Here, we evaluated the effects of a phospholipase D1 (PLD1)-selective inhibitor (VU0155069) against sepsis and inflammasome activation. VU0155069 strongly enhances survival rate in cecal ligation and puncture (CLP)-induced sepsis by inhibiting lung inflammation, leukocyte apoptosis, and the production of proinflammatory cytokines, especially IL-1β. VU0155069 also significantly blocked IL-1β production, caspase-1 activation, and pyroptosis caused by several inflammasome-activating signals in the bone marrow-derived macrophages (BMDMs). However, VU0155069 did not affect LPS-induced activation of signaling molecules such as MAPK, Akt, NF-κB, and NLRP3 expression in the BMDMs. VU0155069 also failed to affect mitochondrial ROS generation and calcium increase caused by nigericin or ATP, and subsequent ASC oligomerization caused by several inflammasome-activating signals. VU0155069 indirectly inhibited caspase-1 activity caused by LPS + nigericin in BMDMs independent of PLD1 activity. We demonstrated that a PLD1 inhibitor, VU0155069, shows anti-septic activity as well as inflammasome-inhibiting effects. Our results suggest that VU0155069 can be considered a novel inflammasome inhibitor.

scholarly journals ER Stress Activates the NLRP3 Inflammasome: A Novel Mechanism of Atherosclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Xinnong Chen ◽  
Xiaochen Guo ◽  
Qihui Ge ◽  
Yixuan Zhao ◽  
Huaiyu Mu ◽  
...  
Keyword(s):  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Ros Generation ◽  
Macromolecular Complex ◽  
Inflammasome Activation ◽  
Cellular Processes ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) is an important organelle that regulates several fundamental cellular processes, and ER dysfunction has implications for many intracellular events. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is an intracellularly produced macromolecular complex that can trigger pyroptosis and inflammation, and its activation is induced by a variety of signals. ER stress has been found to affect NLRP3 inflammasome activation through multiple effects including the unfolded protein response (UPR), calcium or lipid metabolism, and reactive oxygen species (ROS) generation. Intriguingly, the role of ER stress in inflammasome activation has not attracted a great deal of attention. In addition, increasing evidence highlights that both ER stress and NLRP3 inflammasome activation contribute to atherosclerosis (AS). AS is a common cardiovascular disease with complex pathogenesis, and the precise mechanisms behind its pathogenesis remain to be determined. Both ER stress and the NLRP3 inflammasome have emerged as critical individual contributors of AS, and owing to the multiple associations between these two events, we speculate that they contribute to the mechanisms of pathogenesis in AS. In this review, we aim to summarize the molecular mechanisms of ER stress, NLRP3 inflammasome activation, and the cross talk between these two pathways in AS in the hopes of providing new pharmacological targets for AS treatment.

scholarly journals Intranasal Application of Budesonide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Nucleotide-Binding Oligomerization Domain-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Liang Dong ◽  
Yu-Hang Zhu ◽  
De-Xing Liu ◽  
Juan Li ◽  
Peng-Cheng Zhao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Nlrp3 Inflammasome ◽  
Lethal Dose ◽  
Survival Rates ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Receptor Family ◽  
Oligomerization Domain

Aim. To investigate the protective effects of budesonide against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in a murine model and its underlying mechanism. Methods. Adult male C57BL/6 mice were divided into three groups: control, ALI, and ALI + budesonide groups. LPS (5 mg/kg) was intratracheally injected to induce ALI in mice. Budesonide (0.5 mg/kg) was intranasally given 1 h before LPS administration in the ALI + budesonide group. Twelve hours after LPS administration, all mice were sacrificed. Hematoxylin-eosin staining and pathological scores were used to evaluate pathological injury. Bronchoalveolar lavage was performed. The numbers of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid (BALF) were counted. Enzyme-linked immunosorbent assay was employed to detect the proinflammatory cytokines in BALF and serum, including tumor necrosis factor- (TNF-) α, monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 1β. The expression of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was detected by western blotting. A lethal dose of LPS (40 mg/kg, intraperitoneally) was injected to evaluate the effects of budesonide on survival rates. Results. Budesonide pretreatment dramatically attenuated pathological injury and reduced pathological scores in mice with ALI. Budesonide pretreatment obviously reduced the numbers of total cells, neutrophils, and macrophages in the BALF of mice with ALI. Additionally, budesonide dramatically reduced TNF-α and MCP-1 expression in the BALF and serum of mice with ALI. Budesonide significantly suppressed NLRP3 and pro-caspase-1 expression in the lung and reduced IL-1β content in the BALF, indicating that budesonide inhibited the activation of the NLRP3 inflammasome. Furthermore, we found that budesonide improved the survival rates of mice with ALI receiving a lethal dose of LPS. Conclusion. Suppression of NLRP3 inflammasome activation in mice via budesonide attenuated lung injury induced by LPS in mice with ALI.

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