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Obesity is generally associated with low-grade inflammation. Adipose tissue macrophages (ATMs) orchestrate metabolic inflammation. The classical (M1-like) or alternative (M2-like) activation of ATMs is functionally coupled with the metabolic status of fat tissues. It has been found that T-cell immunoglobulin- and mucin-domain-containing molecule-4 (Tim-4) inhibits inflammation by regulating macrophages. However, the exact role of Tim-4 in macrophage polarization and obesity remains unknown. Here, we identified Tim-4 as a critical switch governing macrophage M1/M2 polarization and energy homeostasis. Tim-4 deletion led to spontaneous obesity in elder mice and promoted obesity severity of db/db mice. Obesity microenvironment enhanced the expression of Tim-4 in white adipose tissue and ATMs. In vitro, we detected an increase in M1-like cells and decrease in M2-like cells in both peritoneal macrophages and bone marrow-derived macrophages from Tim-4 knockout mice. Mechanistically, we demonstrated that Tim-4 promoted M2-like macrophages polarization via suppressing nuclear factor kappa B (NF-κB) signaling pathway. In addition, we found that Tim-4 promoted TLR4 internalization, which might contribute to regulation of NF-κB signaling. Collectively, these results indicated that Tim-4 maintained adipose tissue homeostasis by regulating macrophage polarization via NF-κB pathway, which would provide a new target for obesity intervention. © 2022 John Wiley & Sons Ltd.

Citation

Lu Ding, Yan Liang, Yuzhen Wang, Zheng Tong, Wen Liu, Siyu Tan, Jie Zhang, Yingchun Wang, Zhuanchang Wu, Xiaohong Liang, Chunhong Ma, Lifen Gao. T-cell immunoglobulin- and mucin-domain-containing molecule-4 maintains adipose tissue homeostasis by orchestrating M2 macrophage polarization via nuclear factor kappa B pathway. Immunology. 2023 Jan;168(1):49-62

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PMID: 35908188

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