A COMMON CD300F POLYMORPHISM (R218Q) CONFERS GAIN-OF-FUNCTION IN MACROPHAGE APOPTOTIC CELL CLEARANCE

Macrophages play a crucial role in maintaining tissue homeostasis throughout the organism's life cycle. CD300f, a dual activating/inhibitory receptor expressed on myeloid cells, is essential for metabolic fitness and metabolic reprogramming in macrophage populations, and promotes apoptotic cell (AC) clearance through recognition of phosphatidylserine. A common nonsynonymous SNP in CD300f (rs2034310, R218Q; 20–30% prevalence depending on ethnicity) disrupts PKCδ-mediated phosphorylation of threonine 221 and has been linked to reduced risk of depression in women and anxiety in men. Here, we investigated the functional impact of this variant in macrophages by assessing phagocytic capacity and associated signaling pathways. Across multiple macrophage models (including CD300f-WT and CD300f R218Q in THP1 differentiated macrophages, bone marrow-derived macrophages from humanized mice, and peripheral blood mononuclear cells- differentiated macrophages), the CD300f-R218Q variant exhibited markedly reduced phosphorylation of threonine 221 following stimulation with PMA, apoptotic cells and LPS stimulation. Interestingly, CD300f-R218Q macrophages displayed enhanced phagocytosis of ACs and increased degradation of internalized ACs percentage compared with WT cells. Moreover, CD300f-R218Q macrophages showed elevated levels of lysosomal acid lipase and glucocerebrosidase (GCase) levels after AC uptake, consistent with increased lysosomal metabolic activity. Antibody blockade of CD300f partially reduced phagocytosis in both WT and R218Q macrophages, indicating that AC binding of CD300f triggers tyrosine-based signaling motifs that promote clearance. Collectively, these findings demonstrate that the CD300f-R218Q variant confers a gain-of-function in macrophage phagocytosis, highlighting the importance of genetic variation in CD300f for immune regulation and suggesting a potential role in modulating disease susceptibility and resilience.