TIM-4 inhibits NLRP3 inflammasome via the LKB1/AMPKA pathway in macrophages

Wen Liu, Fuxiang Bai, Hongxing Wang, Yan Liang, Xianhong Du, Cui Liu, Dejian Cai, Jiali Peng, Guangming Zhong, Xiaohong Liang, Chunhong Ma, Lifen Gao

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by excessive inflammation and lipid deposition, is one of the most common metabolic liver diseases. The expression of NLRP3 inflammasome in macrophages is significantly increased in NAFLD, and its activation aggravates NAFLD greatly. Tim-4, as the phosphatidylserine (PS) receptor, is expressed highly in macrophages, and macrophage Tim-4 inhibits inflammation under various conditions of immune activation. However, the precise role of Tim-4 in NLRP3 inflammasome regulation and NAFLD pathogenesis remains completely unknown. Using NAFLD mice models, we confirmed that the expression of Tim-4 was increased in liver tissues by Western blot, real-time PCR, immunohistochemistry, and immunofluorescence, especially higher expression in liver macrophages, and Tim-4 knockout mice displayed more severe liver inflammation and hepatic steatosis than controls in NAFLD mice model. In vitro, we found that Tim-4 could inhibit NLRP3 inflammasome activation, and the inhibition was dependent on PS binding domain in the IgV domain. Mechanistically, Tim-4 induced the degradation of NLRP3 inflammasome components through activating AMPKa-mediated autophagy. Specifically, Tim-4 promoted AMPKa phosphorylation by interacting with LKB1 and AMPKa. In addition, PS binding motif was responsible for Tim-4–mediated AMPKa and LKB1 interaction. In conclusion, NAFLD microenvironments upregulate Tim-4 expression in macrophages, and elevated Tim-4, in turn, suppresses NLRP3 inflammasome activation by activating LKB1/AMPKa-mediated autophagy, thereby ameliorating the release of IL-1b and IL-18. Collectively, this study unveils the novel function of Tim-4 in suppressing NLRP3 inflammasome, which would shed new lights on intervention of NAFLD or inflammatory liver diseases by targeting Tim-4.

Original languageEnglish (US)
Pages (from-to)990-1000
Number of pages11
JournalJournal of Immunology
Volume203
Issue number4
DOIs
StatePublished - Aug 15 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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