NR4A1-dependent Ly6Clowmonocytes contribute to reducing joint inflammation in arthritic mice through Treg cells.

Abstract

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 lymphocyte antigen 6C (Ly6Clow) monocytes, we found that inflammatory Ly6Chighmonocytes 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 Ly6Clowmonocytes were restored. Adoptive transfer of Ly6Clowmonocytes in arthritic NR4A1-/-mice treated with Csn-B reduces joint inflammation, supporting the regulatory role of Ly6Clowsubset on disease development. Our results also reveal that administration of Csn-B to arthritic mice enhances levels of circulating CD4+CD25+FoxP3+Treg cells, a process requiring the presence of Ly6Clowmonocytes. Together, these data indicate that Ly6Chighmonocytes are involved in the initiation and progression of arthritis and Ly6Clowmonocytes contribute to reduce joint inflammation through the mobilization of Treg cells.