Tim-4 protects mice against lipopolysaccharide-induced endotoxic shock by suppressing the NF-κB signaling pathway

Xu, Lixiang; Zhao, Peiqing; Xu, Yong; Gao, L.J.; Wang, Hongxing; Jia, Xiaoxia; Ma, Hong-xin; Liang, Xiaoxong; Ma, Chunxong; Gao, Lifen

doi:10.1038/labinvest.2016.94

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…It was reported that TIM‐4 inhibited cytokine production via NF‐κB signalling pathway and had no effect on STAT3 phosphorylation, while IL‐6 could increase the activation of NF‐κB and STAT3 signalling pathway . We then tested the changes of these signal molecules in IL‐6‐induced up‐regulation of TIM‐4 in lung cancer cells with NF‐κB inhibitor or STAT3 inhibitor, respectively.…”

Section: Resultsmentioning

confidence: 99%

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

Wang

Bai

et al. 2020

Cell Proliferation

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Objectives Interleukin‐6 (IL‐6) is critical for the development of non‐small‐cell lung cancer (NSCLC). Recently, we identified T‐cell immunoglobulin domain and mucin domain 4 (TIM‐4) as a new pro‐growth player in NSCLC progression. However, the role of TIM‐4 in IL‐6‐promoted NSCLC migration, invasion and epithelial‐to‐mesenchymal transition (EMT) remains unclear. Materials and Methods Expressions of TIM‐4 and IL‐6 were both evaluated by immunohistochemical staining in NSCLC tissues. Real‐time quantitative PCR (qPCR), Western blot, flow cytometry and RT‐PCR were performed to detect TIM‐4 expression in NSCLC cells with IL‐6 stimulation. The roles of TIM‐4 in IL‐6 promoting migration and invasion of NSCLC were detected by transwell assay. EMT‐related markers were analysed by qPCR and Western blot in vitro, and metastasis was evaluated in BALB/c nude mice using lung cancer metastasis mouse model in vivo. Results High IL‐6 expression was identified as an independent predictive factor for TIM‐4 expression in NSCLC tissues. NSCLC patients with TIM‐4 and IL‐6 double high expression showed the worst prognosis. IL‐6 promoted TIM‐4 expression in NSCLC cells depending on NF‐κB signal pathway. Both TIM‐4 and IL‐6 promoted migration, invasion and EMT of NSCLC cells. Interestingly, TIM‐4 knockdown reversed the role of IL‐6 in NSCLC and IL‐6 promoted metastasis of NSCLC by up‐regulating TIM‐4 via NF‐κB. Conclusions TIM‐4 involves in IL‐6 promoted migration, invasion and EMT of NSCLC.

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Section: Resultsmentioning

confidence: 99%

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

Wang

Bai

et al. 2020

Cell Proliferation

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“…Tim-4 could also suppress nitric oxide (NO) production in LPS-or IFN-γ-activated macrophages (14). Furthermore, Tim-4 was shown to protect mice from ConA-induced liver injury or LPS-induced septic shock by inhibiting pro-inflammatory cytokines such as IL-6 and TNFα (15,35). Although Con A-induced liver injury is a T cellmediated autoimmune hepatitis model (36), it has been found that Kupffer cells are involved in the initiation and propagation of liver damages (37), suggesting that Tim-4 expressed on macrophages might attenuate the priming and activation of T cell responses in Con A-induced hepatitis.…”

Section: Macrophagesmentioning

confidence: 99%

Tim-4 in Health and Disease: Friend or Foe?

Liang

et al. 2020

Front. Immunol.

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T-cell immunoglobulin and mucin domain containing 4 (Tim-4) is a phosphatidylserine receptor and is selectively expressed on antigen presenting cells. Recently, Tim-4 was reported to be expressed on iNKT cells, B1 cells, and tumor cells, suggesting it has multiple biological functions. In this review, we mainly summarize the expression and regulation of Tim-4 in immune cells including T cells, macrophages, dendritic cells, NKT cells, B cells, and mast cells. The expression of Tim-4 in these cells implies that Tim-4 might participate in immune related diseases. Emerging evidence emphasizes a substantial role for Tim-4 in maintaining homeostasis by regulating various immune responses, including viral infection, allergy, autoimmunity, and tumor immunity. Here, we collectively evaluated the role of Tim-4 in health and diseases. This summary will be extremely useful to fully understand the function of Tim-4 in the pathogenesis of immune related diseases, which would provide novel clues for the diagnosis and treatment of diseases.

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“…Tim-4, identified as a phosphatidylserine (PS) receptor mediating the uptake of apoptotic cells, is expressed highly in dendritic cells and macrophages (12). We have reported that macrophage Tim-4 inhibits inflammation under various conditions of immune activation (13)(14)(15). Recently, genome-wide association studies have identified that the relative expression of Tim-4 in liver tissue of rats exposed to a highfat diet (HFD) is 3.10-fold higher than observed in normal diet controls (16), and certain single nucleotide polymorphisms in Tim-4 show associations with lipid traits (17,18).…”

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confidence: 99%

Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages

Liu

Bai

Wang

et al. 2019

The Journal of Immunology

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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.

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Tim-4 protects mice against lipopolysaccharide-induced endotoxic shock by suppressing the NF-κB signaling pathway

Cited by 11 publications

References 42 publications

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

IL‐6 promotes metastasis of non‐small‐cell lung cancer by up‐regulating TIM‐4 via NF‐κB

Tim-4 in Health and Disease: Friend or Foe?

Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages

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