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

Abstract 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)