MS4A6D Promotes carrageenan-induced footpad swelling in mice through enhancing macrophages-derived inflammation

Our previous work has demonstrated that the tetraspan MS4A6D interacts with MHC-II to be a complex that promotes macrophage activation (Mol Immunol. 2023; 160: 121–132), however, the exact role of MS4A6D in controlling macrophage-derived inflammation is still poorly understood. Here, we showed that Ms4a6d-deficient (Ms4a6d-/-) mice manifested a lower level of footpad swelling induced by subcutaneous injection of 100 μL of 1% Carrageenan (CGN, w/v) plus CaCl2 (50 mM), a phenomenon that is similar to Nlrp3-/-, Casp-1-/-, and Ilr1-/- mice. Mechanistically, F4/80+ macrophages infiltrated in the footpad tissues of the Ms4A6d-/- mice was significantly lower than that of the WT littermates, leading to dramatically lower levels of proIL-1β in vivo. Moreover, macrophages from Ms4a6d-/- mice also showed a dramatical reduction of Il-1β secretion following NLRP3 inflammsome activation in vitro. Interestingly, both Ms4a6dC237G mutant (Interruption of MS4A6D homodimerization) and Ms4a6dY241G mutant (deletion of heITAM motif) mice also significantly inhibited CGN-induced footpad swelling due to lower levels of Il-1β secretion in vivo. Collectively, MS4A6D aggravates CGN-induced footpad swelling in mice by enhancing NLRP3 inflammasome in macrophages and inducing the release of IL-1β, indicating that MS4A6D promotes the progression of acute inflammation.