CD14-deficiency in osteoclasts reveals differences in Type I Interferon autocrine signaling and antigen presentation-related gene expression 4402

Description Increased bone deposition and an influx of immune cells in the subchondral bone are primary characteristics of Osteoarthritis (OA). We have shown that with CD14-deficiency (TLR4 co-receptor), mice are protected from OA symptoms, specifically subchondral bone deposition. Understanding that myeloid lineage osteoclasts (OCs) are bone-resorbing APCs, we hypothesized that depletion of CD14 would protect against TLR4-dependent inhibition of osteoclastogenesis and modulate antigen presentation in OCs. In vitro OC-genesis assay showed that CD14 deficient (KO) osteoclasts differentiated faster due to decreased Type I Interferon (TII) autocrine signaling. Further, upon RANKL-stimulation, osteoclast precursors begin releasing S100A8/9 proteins, a TLR4 ligand potentially responsible for the TII production in WT cells. To understand differences in antigen presentation, we performed bulk RNA sequencing. Compared to WT, MHCI-related genes (9/10 surveyed) were downregulated in both CD14KO macrophages (MACs) and CD14KO OCs, while MHCII-related genes (4/4 surveyed) were downregulated in CD14KO macrophages and upregulated in CD14KO OCs. PD-L1 was downregulated in CD14KO MACs but unchanged in OCs. Lastly, CD14-KO decreased the expression of CCL5 and CXCL10 in MACs and OCs, while increasing the expression of TGFB in OCs but not MACs. This data suggests that CD14-deficiency increases OC-genesis while modulating antigen presentation properties of osteoclasts and their precursors. Funding Sources NIH, Philadelphia VAMC Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)