Vsig4, or V-set and immunoglobulin domain containing 4, is a type I transmembrane receptor exclusively expressed in a subset of tissue-resident macrophages. It plays a pivotal role in clearing C3-opsonized pathogens and their byproducts from the circulation, maintaining immune homeostasis by suppressing complement pathways or T-cell activation and inducing regulatory T-cell differentiation [2]. It is also involved in the regulation of the NLRP3 inflammasome through interaction with MS4A6D to form a surface signaling complex, leading to the repression of Nlrp3 and Il-1β transcription [3].

In mouse models, Vsig4 knockout reveals its role in multiple disease processes. In acute myocardial infarction, Vsig4 promotes scar formation, orchestrates the myocardial inflammatory response, and promotes TGF-β1 and IL-10. Hypoxia promotes Vsig4 expression in M2 macrophages, which leads to the conversion of cardiac fibroblasts to myofibroblasts [1]. In experimental autoimmune encephalomyelitis and dextran sulfate sodium-induced colitis, Vsig4-deficient mice show exaggerated NLRP3 and IL-1β expression, resulting in more severe disease [3]. In glioblastoma, silencing Vsig4 inhibits tumor cell proliferation, invasion, and migration, and promotes pyroptosis by regulating the JAK2/STAT3 pathway [4]. In aggressive cancers like anaplastic thyroid cancer and pancreatic cancer, targeting Vsig4 + tumor-associated macrophages by Vsig4 deficiency or blockade limits tumor growth and metastasis, and restores antigen presentation and activates antigen-specific CD8+ T cells [5].

In conclusion, Vsig4 is crucial for immune homeostasis and is involved in various disease conditions such as myocardial infarction, inflammatory diseases, and cancers. Gene knockout mouse models have been instrumental in revealing its role in these processes, providing potential therapeutic targets for treating related diseases.

References:

1. Wang, Yan, Zhang, Yu, Li, Jiao, Ge, Junbo, Shi, Bei. 2023. Hypoxia Induces M2 Macrophages to Express VSIG4 and Mediate Cardiac Fibrosis After Myocardial Infarction. In Theranostics, 13, 2192-2209. doi:10.7150/thno.78736. https://pubmed.ncbi.nlm.nih.gov/37153746/

2. Liu, Bei, Cheng, Li, Gao, Honghao, Gong, Taiqian, Huang, Wenrong. 2022. The biology of VSIG4: Implications for the treatment of immune-mediated inflammatory diseases and cancer. In Cancer letters, 553, 215996. doi:10.1016/j.canlet.2022.215996. https://pubmed.ncbi.nlm.nih.gov/36343787/

3. Huang, Xiaoyong, Feng, Zeqing, Jiang, Yuanzhong, Wu, Yuzhang, Chen, Yongwen. 2019. VSIG4 mediates transcriptional inhibition of Nlrp3 and Il-1β in macrophages. In Science advances, 5, eaau7426. doi:10.1126/sciadv.aau7426. https://pubmed.ncbi.nlm.nih.gov/30662948/

4. Zheng, Congying, Mao, Chengliang, Tang, Kai, Shu, Hang. 2023. VSIG4 Silencing Inhibits Glioblastoma Growth by Regulating the JAK2/STAT3 Pathway. In Neuropsychiatric disease and treatment, 19, 1397-1408. doi:10.2147/NDT.S406782. https://pubmed.ncbi.nlm.nih.gov/37292180/

5. Pan, Zongfu, Chen, Jinming, Xu, Tong, Ge, Minghua, Huang, Ping. 2025. VSIG4+ tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1. In Journal of experimental & clinical cancer research : CR, 44, 45. doi:10.1186/s13046-025-03303-z. https://pubmed.ncbi.nlm.nih.gov/39920772/