TY - JOUR
T1 - TIM-4 inhibits NLRP3 inflammasome via the LKB1/AMPKA pathway in macrophages
AU - Liu, Wen
AU - Bai, Fuxiang
AU - Wang, Hongxing
AU - Liang, Yan
AU - Du, Xianhong
AU - Liu, Cui
AU - Cai, Dejian
AU - Peng, Jiali
AU - Zhong, Guangming
AU - Liang, Xiaohong
AU - Ma, Chunhong
AU - Gao, Lifen
N1 - Publisher Copyright:
© 2019 American Association of Immunologists. All rights reserved.
PY - 2019/8/15
Y1 - 2019/8/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070357028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070357028&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1900117
DO - 10.4049/jimmunol.1900117
M3 - Article
C2 - 31263038
AN - SCOPUS:85070357028
SN - 0022-1767
VL - 203
SP - 990
EP - 1000
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -