Timd4, also known as T cell immunoglobulin and mucin domain containing 4, is a gene with diverse functions. It is involved in processes such as apoptotic cell clearance, phagocytosis, and macrophage-related activities. In macrophages, it may be associated with the Wnt/β-catenin pathway, and has been linked to the regulation of lipid metabolism as indicated by its association with triglyceride levels [1,2].

In a mouse model of periodontitis, Tim4 deficiency led to a reduction in CD301b+ macrophages and aggravated alveolar bone resorption, suggesting that Timd4 controls CD301b+ macrophages through the p38 MAPK signaling pathway [3]. In broad-spectrum antibiotics-treated mice, the down-regulation of Timd4 in large peritoneal macrophages (LPMs) impaired efferocytosis, and oral butyrate rescued this effect, highlighting its role in homeostatic efferocytosis [4]. In the context of anti-tumor immunity, Tim-4+ cavity-resident macrophages sequestered anti-tumor CD8+ T cells and suppressed their proliferation, and Tim-4 blockade enhanced anti-tumor efficacy in mouse models of immunotherapy [5].

In conclusion, Timd4 plays crucial roles in multiple biological processes including macrophage-mediated functions, efferocytosis, and anti-tumor immunity. The use of gene-knockout mouse models has been instrumental in revealing these functions, providing insights into its potential as a therapeutic target in diseases such as periodontitis, inflammatory diseases related to efferocytosis, and cancer immunotherapy.

References:

1. Li, Yi, Zhang, Pei-Yi, Yang, Zhao-Wen, Ma, Fang, Li, Fa-Xin. 2020. TIMD4 exhibits regulatory capability on the proliferation and apoptosis of diffuse large B-cell lymphoma cells via the Wnt/β-catenin pathway. In The journal of gene medicine, 22, e3186. doi:10.1002/jgm.3186. https://pubmed.ncbi.nlm.nih.gov/32187802/

2. Khounphinith, Eksavang, Yin, Rui-Xing, Cao, Xiao-Li, Wu, Jin-Zhen, Li, Hui. 2019. TIMD4 rs6882076 SNP Is Associated with Decreased Levels of Triglycerides and the Risk of Coronary Heart Disease and Ischemic Stroke. In International journal of medical sciences, 16, 864-871. doi:10.7150/ijms.31729. https://pubmed.ncbi.nlm.nih.gov/31337960/

3. Wang, Ziming, Zeng, Hao, Wang, Can, Zhao, Qin, Zhang, Yufeng. 2024. Tim4 deficiency reduces CD301b+ macrophage and aggravates periodontitis bone loss. In International journal of oral science, 16, 20. doi:10.1038/s41368-023-00270-z. https://pubmed.ncbi.nlm.nih.gov/38418808/

4. Saavedra, Pedro H V, Trzeciak, Alissa J, Lipshutz, Allie, Rudensky, Alexander Y, Perry, Justin S A. 2024. Broad-spectrum antibiotics disrupt homeostatic efferocytosis. In Nature metabolism, 6, 1682-1694. doi:10.1038/s42255-024-01107-7. https://pubmed.ncbi.nlm.nih.gov/39122784/

5. Chow, Andrew, Schad, Sara, Green, Michael D, Rudin, Charles M, Merghoub, Taha. 2021. Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity. In Cancer cell, 39, 973-988.e9. doi:10.1016/j.ccell.2021.05.006. https://pubmed.ncbi.nlm.nih.gov/34115989/