Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages

Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macropha...

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Vydáno v:	PloS one Ročník 11; číslo 9; s. e0155076
Hlavní autoři:	Ke, Ping, Shao, Bo-Zong, Xu, Zhe-Qi, Wei, Wei, Han, Bin-Ze, Chen, Xiong-Wen, Su, Ding-Feng, Liu, Chong
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 09.09.2016 Public Library of Science (PLoS)
Témata:	AMP-Activated Protein Kinases - metabolism Animals Attenuation Autophagy Autophagy - genetics Autophagy - immunology Biology and Life Sciences Cannabinoid CB2 receptors Cell activation Cell death Cell Line Cells, Cultured Colitis Colitis - chemically induced Colitis - genetics Colitis - metabolism Colitis - pathology Colon Dextran Sulfate - adverse effects Experiments House mouse IL-1β Inflammasomes Inflammasomes - metabolism Inflammation Inflammatory bowel disease Infrared imaging systems Interleukin-1beta - metabolism Laboratory animals Leucine Lipopolysaccharides Lipopolysaccharides - immunology Macrophage Activation Macrophages Macrophages - metabolism Macrophages, Peritoneal - metabolism Male Medicine and Health Sciences Mice Mice, Knockout NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Peritoneum Phagocytosis Pharmacology Pharmacy Polymerase chain reaction Proteins Receptor, Cannabinoid, CB2 - genetics Receptor, Cannabinoid, CB2 - metabolism Ribosomal Protein S6 Kinases, 70-kDa - metabolism Rodents Signal Transduction Signaling siRNA TOR protein TOR Serine-Threonine Kinases - metabolism
ISSN:	1932-6203, 1932-6203
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Shrnutí:	Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: CL DFS.Performed the experiments: PK BZS ZQX WW BZH.Analyzed the data: PK CL.Contributed reagents/materials/analysis tools: PK BZS.Wrote the paper: CL BZS XWC.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0155076