A pathogenic Th17/CD38+ macrophage feedback loop drives inflammatory arthritis through TNFa

The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. Here, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations like those found in human RA. Notably, murine macrophage subtypes like those in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNFa induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis and their depletion or blockade via TNFa-neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNFa to drive inflammatory arthritis. scRNA-Seq analysis of FACS-sorted live synovial cells isolated from naïve mice (two replicates) or from mice at day 6, 14, or 25 of GPI-induced arthritis (one replicate per time point).