Ms4a6d, a tetraspan gene, is mainly expressed in mononuclear phagocytes, and its gene transcript is regulated by the transcription factor NK2 homeobox-1 (NKX2-1). It functions as a coreceptor of MHC class II antigen (MHC-II), forming a surface signaling complex under acute inflammatory conditions. This complex activates SYK-CREB signaling cascades, influencing the transcription of proinflammatory genes and mitochondrial reactive oxygen species (mtROS) secretion, thus playing a crucial role in macrophage-derived inflammation [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 injection compared to wild-type mice due to reduced F4/80 + macrophage infiltration and Il-1β secretion [2]. Moreover, both Ms4a6dC237G and Ms4a6dY241G mutation mice, which disrupt MS4A6D homodimerization and the ITAM motif respectively, phenocopy Ms4a6d-/-animals in preventing endotoxin lethality and inhibiting carrageenan-induced footpad swelling [1,2].

In conclusion, Ms4a6d plays a significant role in promoting macrophage-derived inflammation. The study of Ms4a6d-/-and mutant mouse models has revealed its key role in acute inflammatory conditions, highlighting it as a potential novel target for treating macrophage-associated disorders [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/