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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

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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.

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Funding

This work was supported by grants from the National Natural and Science Foundation of China (81970532, 81770603).

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Authors and Affiliations

  1. Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China

    Lei Hou, Zhi Zhang, Le Yang, Na Chang, Xinhao Zhao, Xuan Zhou, Lin Yang & Liying Li

  2. Beijing, China

    Liying Li

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  1. Lei Hou
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  2. Zhi Zhang
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  3. Le Yang
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  4. Na Chang
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  5. Xinhao Zhao
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  7. Lin Yang
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Contributions

Conceptualization, Liying Li; Methodology, Lei Hou; Funding acquisition, Liying Li and Na Chang; Formal analysis, Lei Hou; Investigation, Lei Hou, Zhi Zhang, Xinhao Zhao. and Xuan Zhou; Writing-original draft preparation, Lei Hou, Le Yang, and Na Chang; Writing-review and editing, Liying Li; project administration, Lin Yang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Liying Li.

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All animal work conformed to the Ethics Committee of Capital Medical University and were in accordance with the approved guidelines (approval AEEI-2014-131).

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Hou, L., Zhang, Z., Yang, L. et al. NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα(12/13)/MAPK signaling pathway. J Mol Med 99, 273–288 (2021). https://doi.org/10.1007/s00109-020-02032-4

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