Our previous research demonstrated that the tetraspan MS4A6D is an adapter of VSIG4 that controls NLRP3 inflammasome activation (Sci Adv. 2019: eaau7426); however, the expression, distribution and biofunction of MS4A6D are still poorly understood. Here, we showed that MS4A6D is restricted to mononuclear phagocytes and that its gene transcript is controlled by the transcription factor NK2 homeobox-1 (NKX2–1). Ms4a6d-deficient (Ms4a6d^-/-) mice showed normal macrophage development but manifested a greater survival advantage against endotoxin (lipopolysaccharide) challenge. Mechanistically, MS4A6D homodimers crosslinked with MHC class II antigen (MHC-II) to form a surface signaling complex under acute inflammatory conditions. MHC-II occupancy triggered Tyr²⁴¹ phosphorylation in MS4A6D, leading to activation of SYK-CREB signaling cascades, further resulting in augmenting the transcription of proinflammatory genes (Il1b, Il6 and Tnfa) and amplifying the secretion of mitochondrial reactive oxygen species (mtROS). Deletion of Tyr²⁴¹ or interruption of Cys²³⁷-mediated MS4A6D homodimerization in macrophages alleviated inflammation. Importantly, both Ms4a6d^C237G and Ms4a6d^Y241G mutation mice phenocopied Ms4a6d^-/- animals to prevent endotoxin lethality, highlighting MS4A6D as a novel target for treating macrophage-associated disorders.