Vsig4, also known as V-set and immunoglobulin domain containing 4, is a type I transmembrane receptor uniquely expressed in a subset of tissue-resident macrophages [2]. It plays a pivotal role in maintaining immune homeostasis, for example, by clearing C3-opsonized pathogens and their byproducts from the circulation, suppressing complement pathways or T-cell activation, and inducing regulatory T-cell differentiation [2]. It is also involved in multiple signaling pathways, such as the JAK2-STAT3-A20 cascades through interaction with MS4A6D [3].

In acute myocardial infarction (AMI) mouse models, Vsig4 knockout and adoptive bone marrow transfer chimeric models showed that Vsig4 promotes scar formation, orchestrates the myocardial inflammatory response, and promotes TGF-β1 and IL-10. Hypoxia promotes Vsig4 expression in cultured bone marrow M2 macrophages, leading to the conversion of cardiac fibroblasts to myofibroblasts [1]. In experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis mouse models, Vsig4-deficient macrophages exhibit increased Nlrp3 and Il-1β transcription, caspase-1 activation, pyroptosis, and interleukin-1β (IL-1β) secretion. Agonistic Vsig4 antibodies show therapeutic efficacy in mouse EAE [3]. In glioblastoma (GBM) xenograft tumor models, silencing Vsig4 inhibits tumor cell proliferation, invasion, and migration, and promotes pyroptosis by regulating the JAK2/STAT3 signaling pathway [4].

In conclusion, Vsig4 is crucial for immune homeostasis and is involved in various disease processes. Gene knockout mouse models have been instrumental in revealing its role in AMI, EAE, DSS-induced colitis, and GBM, providing potential immunomodulatory therapeutic avenues for these 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/