Volume 169, May 2024, Pages 28-36Author links open overlay panel, , , , , , , , , , Highlights•

Ms4a6d-/- mice manifested a lower level of footpad swelling induced by subcutaneous injection of CGN plus CaCl2.

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Macrophages from Ms4a6d-/- mice showed dramatically lower levels of proIL-1β, by thus reduced Il-1β secretion following NLRP3 inflammsome was activated in vitro.

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Both Ms4a6dC237G mutant and MS4A6DY241G mutant mice also significantly inhibited CGN-induced footpad swelling due to lower levels of Il-1β secretion in vivo.

Abstract

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.

Section snippetsDown-regulated expression of proIL-1β protein in peritoneal macrophages derived from Ms4a6d-/- mice

Our previous studies have shown that MS4A6D protein is mainly expressed in macrophages (Huang et al., 2019a, Chen et al., 2023a). Macrophages can be functionally categorized into two distinct subgroups, the classically activated M1 type, and the alternatively activated M2 type (Natoli et al., 2021). In response to INF-γ and lipopolysaccharide (LPS), M0 macrophages differentiate into M1-type macrophages, which are mainly involved in the initiation and maintenance of inflammatory responses,

Discussion

The MS4A genome contains 18 molecules on human chromosome 11 and mice chromosome 19, respectively, which produce proteins that regulate innate immunity and malignant transformation and progression of tumors (Eon Kuek et al., 2016). Multiple MS4A proteins are also function as components of Ca2+ channels or Ca2+ channel regulators, for instances, MS4A1 homo-oligomerize into tetramers that positively regulate BCR-induced cytoplasmic Ca2+ mobilization (Li et al., 2003). Among these molecules, mice

Material and Methods

Experimental mice Ms4a6d knockout mice (Ms4a6d-/-) on a C57BL/6 background and Ms4a6dC237G mutation as well as Ms4a6dY241G mutation mice were generated by CRISPR/Cas9 from Cyagen Biosciences (Guangzhou, China). The Nlrp3-/-, Casp-1-/-, and Ilr1-/- mice were purchased from The Jax Lab in the United States. The mice were housed at the Experimental Animal Center of the Army Medical University and fed with a standard laboratory diet. The care of the experimental mice followed the guidelines

CRediT authorship contribution statement

Chenhui Wang: Formal analysis. Jing Guo: Investigation. Zeqing Feng: Investigation, Conceptualization. Qun Xiang: Data curation. Guoning Guo: Validation, Investigation. Lei Fei: Resources, Investigation, Data curation. Yunfei An: Methodology, Investigation. Yongjun Shang: Investigation, Conceptualization. Xiaoyong Huang: Project administration, Methodology. Zhihua Ruan: Project administration, Funding acquisition. Yongwen Chen: Investigation, Funding acquisition, Conceptualization.

Declaration of Competing Interest

The authors declare no financial or commercial conflict of interest.

Acknowledgments

This work was supported by The National Natural Science Foundation of China (NSFC, No. 81971478 and 82001693) and Chongqing Natural Science Fundation (CSTB2022NSCQ－MSX0219).

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