Monocytes in rheumatoid arthritis: Circulating precursors of macrophages and osteoclasts and, their heterogeneity and plasticity role in RA pathogenesis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic, autoimmune and inflammatory disease represented as synovitis, pannus formation, adjacent bone erosions, and joint destruction. The major cells involved in the perpetuation of RA pathogenesis are CD4⁺ T-cells (mainly Th1 cells and Th17 cells), fibroblasts like synoviocytes (FLS), macrophages and B cells. Other autoimmune cells such as dendritic cells, neutrophils, mast cells, and monocytes also contribute to RA pathogenesis. Monocytes are mainly bone marrow (BM) derived cells in the circulation. The chemokine receptors CCR2 and CX3CR1 expressed by monocytes interact with chemokine ligands CCL2 (MCP-1) and CX3CL1 (fractalkine) respectively produced by FLS and this interaction promotes their migration and recruitment into RA synovium. Activated monocytes on their surface exhibit upregulated antigenic expressions such as CD14, CD16, HLA-DR, toll-like receptors (TLRs), and adhesion molecules B1 and B2 integrins. RA monocytes interconnect with other cells in a positive loop manner in the propagation of the rheumatoid process. They skew towards mainly intermediate monocyte subsets (CD14⁺⁺ CD16⁺) which produce proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. Moreover, the predominant intermediate monocytes in RA differentiate into M1-macrophages which play a major role in synovial inflammation. Demonstrations suggest monocytes with CD14⁺ and CD16^- expression (classical monocytes?) differentiate to osteoclasts which are the cells responsible for bone erosion in RA synovial joints. Th17 cells induce the production of RANKL by FLS which promotes osteoclastogenesis. Cytokines mainly TNF-α, IL-1β, and IL-6 amplify osteoclastogenesis. Hence, monocytes are the circulating precursors of macrophages and osteoclasts in RA. AIM OF THE REVIEW: To enlighten the identity of monocytes, the antigenic expression on monocyte surface and their cytokines role in RA. We also emphasize about the chemokine receptors expressed by monocytes subsets and chemotaxis of circulating monocytes into RA synovium. Additionally, we review monocytes as the circulating precursors of macrophages and osteoclasts in RA joints and their heterogeneity and plasticity role in RA.

Keywords: Circulating precursors; Classical monocyte; Intermediate monocyte; Macrophage; Osteoclasts; Proinflammatory cytokine.