NR4A1‐dependent Ly6Clow monocytes contribute to reducing joint inflammation in arthritic mice through Treg cells

Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1−/− mice, which lack patrolling Ly6Clow monocytes, we found that inflammatory Ly6Chigh monocytes contribute to rapid development of arthritis in a serum transfer-induced arthritis (STIA) model. Our experiments suggest that patrolling monocytes do not promote the initiation and progression of arthritis in mice, as severity of symptoms was amplified in NR4A1−/− mice. Moreover, we show that treatment of arthritic wild type (WT) mice with cytosporone B (Csn-B), a NR4A1 specific agonist, significantly reduces severity of disease. Effects of Csn-B were absent in monocyte-depleted mice treated with clodronate until Ly6Clow monocytes were restored. Adoptive transfer of Ly6Clow monocytes in arthritic NR4A1−/− mice treated with Csn-B reduces joint inflammation, supporting the regulatory role of Ly6Clow subset on disease development. Our results also reveal that administration of Csn-B to arthritic mice enhances levels of circulating CD4+CD25+FoxP3+ regulatory T (Treg) cells, a process requiring the presence of Ly6Clow monocytes. Together, these data indicate that Ly6Chigh monocytes are involved in the initiation and progression of arthritis and Ly6Clow monocytes contribute to reduce joint inflammation through the mobilization of Treg cells. This article is protected by copyright. All rights reserved