NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway - PubMed (original) (raw)

. 2021 Feb;99(2):273-288.

doi: 10.1007/s00109-020-02032-4. Epub 2021 Jan 2.

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NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway

Lei Hou et al. J Mol Med (Berl). 2021 Feb.

Abstract

NLRP3 inflammasome-driven inflammation represents a key trigger for hepatic fibrogenesis during cholestatic liver injury. However, whether sphingosine 1-phosphate (S1P) plays a role in NLRP3 inflammasome priming and activation remains unknown. Here, we found that the expression of NLRP3 in macrophages and NLRP3 inflammasome activation were significantly elevated in the liver injured by bile duct ligation (BDL). In vitro, S1P promoted the NLRP3 inflammasome priming and activation via S1P receptor 2 (S1PR2) in bone marrow-derived monocyte/macrophages (BMMs). Focusing on BMMs, the gene silencing of Gα12 or Gα13 by specific siRNA suppressed NLRP3 inflammasome priming and pro-inflammatory cytokine (IL-1β and IL-18) secretion, whereas Gα(i/o) and Gαq were not involved in this process. The MAPK signaling pathways (P38, ERK, and JNK) mediated NLRP3 inflammasome priming and IL-1β and IL-18 secretion, whereas blockage of PI3K, ROCK, and Rho family had no such effect. Moreover, JTE-013 (S1PR2 inhibitor) treatment markedly reduced NLRP3 inflammasome priming and activation in BDL-injured liver. Collectively, S1P promotes NLRP3 inflammasome priming and pro-inflammatory cytokines (IL-1β and IL-18) secretion via the S1PR2/Gα(12/13)/MAPK pathway, which may represent an effective therapeutic strategy for liver disease. KEY MESSAGE: • Hepatic NLRP3 expression was significantly elevated in BMMs of BDL-injured mouse liver. • S1P promoted NLRP3 inflammasome priming and activation in BMMs, depending on the S1PR2/Gα(12/13)/MAPK pathway. • Blockade of S1PR2 by JTE-013 reduced NLRP3 inflammasome priming and activation inflammasome in vivo.

Keywords: G protein–coupled receptors; Liver inflammation; Macrophage; NLR family pyrin domain-containing 3; S1P receptor; Sphingosine 1-phosphate.

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