CX3CR1 And MHCII Define Distinct Synovial Macrophage Populations With Conserved Inflammatory Response Across Mouse Models Of Rheumatoid Arthritis

Macrophages in the synovial lining are critical for the maintenance of healthy tissue while also contributing to the pathogenesis of rheumatoid arthritis (RA). However, the field currently lacks a unifying characterization of synovial macrophage heterogeneity across steady-state and inflammation. Here, we defined 4 transcriptionally distinct populations of synovial macrophages CX3CR1 ⁺ MHCII ^- (lining); CX3CR1 ^- MHCII ^- (interstitial/sublining); CX3CR1 ^- MHCII ⁺ (monocyte-derived); and CX3CR1 ⁺ MHCII ⁺ (infiltrating). The MHCII ^- populations are long-lived and derived from embryonic precursors regardless of localization while the MHCII ⁺ populations differentiate from bone marrow (BM) progenitors dependent on CCR2. We identified conserved activation pathways between acute and chronic mouse models of inflammatory arthritis as well as novel arthritis-associated subpopulations. During peak inflammation, the influx of BM-derived cells was associated with upregulation of monocyte-related genes with concurrent down-regulation of tissue-resident genes. Our results provide a unifying schema for describing synovial macrophages across conditions and pave the way for future studies in modulating transcriptional activity in rheumatoid arthritis.