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

Abstract

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.

Macrophage Sphingosine 1-Phosphate Receptor 2 Blockade Attenuates Liver Inflammation and Fibrogenesis Triggered by NLRP3 Inflammasome

“…In this study, one striking finding was that selective knockdown of the macrophage S1PR 2 replicated the effect of JTE-013 in remarkable attenuation of NLRP3 inflammasome priming and activation during cholestatic liver injury (data not shown). Increasingly, conjugated bile acids have also been implicated in various inflammatory diseases by activating specific nuclear receptors and G protein-coupled receptors (GPCRs), such as S1PR 2 (52,53). In a recent study, researchers found that blockage of S1PR 2 substantially reduced mature IL-1β production and alleviated colonic inflammation induced by conjugated bile acids (53).…”

“…Increasingly, conjugated bile acids have also been implicated in various inflammatory diseases by activating specific nuclear receptors and G protein-coupled receptors (GPCRs), such as S1PR 2 (52,53). In a recent study, researchers found that blockage of S1PR 2 substantially reduced mature IL-1β production and alleviated colonic inflammation induced by conjugated bile acids (53). Our previous studies have documented that a significant proportion (48.2 ± 3.5%) of hepatic non-parenchymal cells are BMMs, supporting the important role of macrophages in BDL-induced liver injury (34).…”

The Biosynthesis, Signaling, and Neurological Functions of Bile Acids

“…S1PR2 is expressed in a variety of tissues and its activation influences various signaling molecules, including adenylyl cyclase, Akt/PKB, and MAPKs [65,67,124]. An unconjugated BA (DCA) and conjugated BA [TCA, TDCA, tauroursodeoxycholic acid (TUDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and glycochenodeoxycholic acid (GCDC)] are ligands for S1PR2, binding of which leads to the activation of ERKs and Akt/PKB [125,126,127].…”

Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells

“…Interestingly, PC3-EV exposure induces an increase in cathepsin B cleaved/active form mediated by ERK1/2 activation as recently shown in DSS-induced colitis where inflammasome activation, superimposed by deoxycolic acid, is triggered by ERK1/2 and cathepsin B [58]. Furthermore, PC3-EVs induce an ERK1/2-dependent lysosomal destabilization.…”