During inflammation or tissue injury, pro-inflammatory mediators attract migratory monocytes to inflammatory sites and monocyte-to-macrophage differentiation occurs to activate macrophages. We report here that PAQR11, a member of the progesterone and AdipoQ receptor family, regulates monocyte-to-macrophage differentiation in vitro and in vivo. Paqr11 gene was highly induced during monocyte-to-macrophage differentiation. Knockdown or deletion of Paqr11 inhibited monocyte differentiation but had little effect on macrophage polarization. Mechanistically, PAQR11 promoted cell survival as apoptosis was increased by Paqr11 knockdown or deletion. Activation of the MAPK signaling pathway was involved in the regulatory role of PAQR11 on monocyte differentiation and cell survival. C/EBPβ regulated the expression of Paqr11 at the transcriptional level. In mice, deletion of Paqr11 gene alleviated progression of collagen-induced rheumatoid arthritis. Thus, these results provide strong evidence that PAQR11 has a function in monocyte-to-macrophage differentiation and such function is related to autoimmune disease in vivo.This article is protected by copyright. All rights reserved.