PMID- 29854830 OWN - NLM STAT- MEDLINE DCOM- 20181011 LR - 20191210 IS - 2314-7156 (Electronic) IS - 2314-8861 (Print) IS - 2314-7156 (Linking) VI - 2018 DP - 2018 TI - Deoxycholic Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Exacerbates DSS-Induced Colitis through Promoting Cathepsin B Release. PG - 2481418 LID - 10.1155/2018/2481418 [doi] LID - 2481418 AB - 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-1beta 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. FAU - Zhao, Shengnan AU - Zhao S AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Gong, Zizhen AU - Gong Z AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Du, Xixi AU - Du X AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Tian, Chunyan AU - Tian C AD - State Key Laboratory of Proteomics, National Center for Proteomics Science (Beijing), Beijing Institute of Radiation Medicine, Beijing, China. AD - National Engineering Research Center for Protein Drugs, Beijing, China. FAU - Wang, Lingyu AU - Wang L AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Zhou, Jiefei AU - Zhou J AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Xu, Congfeng AU - Xu C AD - Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Chen, Yingwei AU - Chen Y AUID- ORCID: 0000-0001-8429-252X AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Cai, Wei AU - Cai W AUID- ORCID: 0000-0002-4355-5693 AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. FAU - Wu, Jin AU - Wu J AUID- ORCID: 0000-0002-3044-1718 AD - Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. AD - Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. LA - eng PT - Journal Article DEP - 20180509 PL - Egypt TA - J Immunol Res JT - Journal of immunology research JID - 101627166 RN - 0 (Alarmins) RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Receptors, Lysosphingolipid) RN - 0 (Sphingosine-1-Phosphate Receptors) RN - 0 (sphingosine-1-phosphate receptor-2, mouse) RN - 005990WHZZ (Deoxycholic Acid) RN - 9042-14-2 (Dextran Sulfate) RN - EC 3.4.22.1 (Cathepsin B) SB - IM MH - Alarmins/immunology MH - Animals MH - Cathepsin B/metabolism MH - Cell Line MH - Colitis/chemically induced/*immunology MH - Deoxycholic Acid/*metabolism MH - Dextran Sulfate MH - Disease Models, Animal MH - Female MH - Humans MH - Inflammasomes/metabolism MH - Inflammatory Bowel Diseases/*immunology MH - Macrophages/*immunology MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Receptors, Lysosphingolipid MH - Signal Transduction MH - Sphingosine-1-Phosphate Receptors PMC - PMC5966668 EDAT- 2018/06/02 06:00 MHDA- 2018/10/12 06:00 PMCR- 2018/05/09 CRDT- 2018/06/02 06:00 PHST- 2017/11/01 00:00 [received] PHST- 2018/01/08 00:00 [accepted] PHST- 2018/06/02 06:00 [entrez] PHST- 2018/06/02 06:00 [pubmed] PHST- 2018/10/12 06:00 [medline] PHST- 2018/05/09 00:00 [pmc-release] AID - 10.1155/2018/2481418 [doi] PST - epublish SO - J Immunol Res. 2018 May 9;2018:2481418. doi: 10.1155/2018/2481418. eCollection 2018.