Ms4a6d, a tetraspan gene, has emerged as a significant player in macrophage-related inflammation. It acts as an adapter of VSIG4 and a coreceptor of MHC class II antigen (MHC-II), regulating NLRP3 inflammasome activation. It is involved in SYK-CREB signaling cascades, which impacts the transcription of proinflammatory genes, and is expressed specifically in mononuclear phagocytes, with its gene transcript controlled by the transcription factor NK2 homeobox-1 (NKX2-1) [1].

Ms4a6d-deficient (Ms4a6d-/ -) mice show normal macrophage development but have a greater survival advantage against endotoxin challenge [1]. They also exhibit a lower level of footpad swelling induced by carrageenan, similar to Nlrp3-/ -, Casp-1-/ -, and Ilr1-/-mice, due to reduced infiltration of F4/80 + macrophages and lower levels of proIL-1β [2]. Moreover, both Ms4a6dC237G and Ms4a6dY241G mutation mice, which disrupt homodimerization or delete the heITAM motif respectively, phenocopy Ms4a6d-/-animals, highlighting the role of Ms4a6d in promoting inflammation [1,2].

In conclusion, Ms4a6d is crucial in promoting macrophage-derived inflammation. The study of Ms4a6d-/-and mutant mouse models has provided insights into its role in inflammatory conditions, suggesting it could be a novel target for treating macrophage-associated disorders such as those related to endotoxin lethality and acute inflammation [1,2].

References:

1. Chen, Yue, Li, Sirui, Huang, Xiaoyong, An, Yunfei, Chen, Yongwen. 2023. Tetraspan MS4A6D is a coreceptor of MHC class II antigen (MHC-II) that promotes macrophages-derived inflammation. In Molecular immunology, 160, 121-132. doi:10.1016/j.molimm.2023.07.003. https://pubmed.ncbi.nlm.nih.gov/37429063/

2. Guo, Jing, Wang, Chenhui, Xiang, Qun, Chen, Yongwen, Huang, Xiaoyong. 2024. MS4A6D Promotes carrageenan-induced footpad swelling in mice through enhancing macrophages-derived inflammation. In Molecular immunology, 169, 28-36. doi:10.1016/j.molimm.2024.03.001. https://pubmed.ncbi.nlm.nih.gov/38493579/