SRA promotes pathogenic Th17 response through inflammatory activation of M-MDSCs in autoimmune arthritis 2645

Description Objectives We have identified the innate pattern recognition scavenger receptor A (SRA) and proinflammatory monocytic myeloid-derived suppressive cells (M-MDSCs) as critical factors involved in pathogenesis of rheumatoid arthritis (RA). Here we investigate the functional regulation of M-MDSCs by SRA in driving a pathogenic T helper 17 (Th17) response. Methods The M-MDSCs in wild-type (WT) or SRA knockout (SRA-/-) arthritic mice were characterized for their phenotypes and their capacity of pro-Th17 differentiation. The role of M-MDSCs in mediating SRA-facilitated Th17 response and disease pathology was examined by depletion or adoptive transfer of M-MDSCs. The SRA-dependent proinflammatory function of M-MDSCs and activation of the NLRP3-IL-1b immune axis was established using neutralizing antibodies or inhibitors. Results The presence of SRA on M-MDSCs defines their pro-inflammatory phenotype. The SRA loss impairs the NLRP3-depedent IL-1b production by M-MDSCs and their ability to potentiate Th17 polarization. Depletion of M-MDSCs abolishes the differences in disease severity in WT and SRA-/- mice. SRA blockade alleviates disease progression associated with attenuation of Th17 response in arthritic mice. Conclusions Our studies provide mechanistic insights into SRA-governed cellular and molecular inflammatory pathways involved in autoimmune arthritis. SRA-targeted therapies may provide new opportunities to manage RA in patients. Funding Sources US Department of Defense Award (W81XWH1910538)