Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis


Pathway Description

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that may affect many tissues and organs, but mainly targets the synovial membrane, cartilage and bone. RA affects about 1% of the world's population, is three times more frequent in women than in men, and is associated with significant disability and increased mortality. The articular manifestations of RA are mediated by extensive infiltration of inflammatory cells into the synovium and proliferation of synovial fibroblasts of the joint lining, leading to the formation of pannus tissue which invades and destroys the articular cartilage and bone.The crucial triggers for the onset of RA are still not completely understood, but genetic and environmental factors both appear to play roles. Several genetic loci (HLA-DR4 and related allotypes of MHC class II, PTPN22, PAD14, CTLA4, FcγR, and various cytokines) have been shown to have an association with the susceptibility and severity of RA. Environmental factors (pathogen, smoking) may also have an impact on the induction and progression of the disease.

The key features of RA are autoimmunity, chronic inflammation and destruction of the cartilage and bones.

After onset of RA, the normally hypocellular synovial membrane becomes hyperplastic (PMID: 17525752). This highly destructive, invasive tissue consists mainly of activated T cells, synovial fibroblasts and macrophages. The altered T cell and B cell signaling in RA mediates the activation of macrophages, synovial fibroblasts and endothelial cells by a cell-contact-mediated mechanism and by the release of cytokines. Activation of these cells in the synovium can also be triggered by Toll-like receptors (TLR), which recognize various pathogen products, as well as self molecules from damaged tissues. In addition, macrophages are activated by immune complex via FcγIII receptors and the complement cascade. Immune complexes are formed when autoantibodies (produced by plasma cells and known as rheumatoid factors) recognize the Fc portion of IgG. Furthermore, IL-6- induced WNT5a activates WNT signaling for autocrine proliferation of synovial fibroblasts in RA and induction of pro-inflammatory cytokines. Activation and release of factors from macrophages, synovial fibroblasts and endothelial cells involved in RA pathogenesis are principally initiated by four main signal transduction pathways, ERK/MAPK pathway, NF-κB pathway, WNT pathway and JAK-STAT pathway. Activation of these pathways is the primary source of pro-inflammatory cytokines and growth factors (e.g. IL-1, IL-6, IL-7, IL-15, IL-16, IL-18, TNF, GM-CSF, RANKL, SDF-1, bFGF, VEGF), chemokines and chemoattractants (e.g. IL-8, MCP-1, RANTES), matrix metalloproteinases (e.g. MMP1, MMP3, MMP13), prostaglandin, and adhesion molecules (e.g. ICAM-1, VCAM-1, SELE).

In turn, all these factors support leukocyte recruitment, infiltration and activation (PMID: 15705634), autoreactive T cell and B cell activation (PMIDs: 18771589, 17525752), synovial fibroblast hyperplasia (PMID: 17525752), angiogenesis (PMIDs: 15705634,17525752,12574387), osteoclast differentiation (PMID: 17525752) and cartilage degradation (PMID: 11167130), which are characteristic of chronic rheumatoid arthritis.


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