Fig. 5.

Pleiotropic actions of the IFN-inducible CXCR3 ligands that may contribute to joint inflammation. Pathogenic processes related to CXCL9 and CXCL10 that were established in vitro and that may contribute to an aberrant synovial microenvironment, include articular cartilage and bone damage through A induction of osteoclastogenesis (directly through their effect on osteoclast progenitor cells and indirectly through induction of RANKL secretion by FLS and CD4⁺ T cells), B stimulation of migration of CXCR3⁺ subchondral progenitor cells, C induction of enzyme secretion that affect bone remodeling by osteoblasts, and D augmenting the activity of MMPs secreted by FLS. In addition, IFN-inducible CXCR3 ligands may facilitate synovial hyperplasia through E alteration of morphology of FLS, stimulation of invasiveness, proliferation and chemotaxis and synovitis through F infiltration of CXCR3⁺ leukocytes, G T_H1 cell polarization and infiltration via CCR3 antagonism, CCL11 scavenging, and desensitization of CXCL12 signaling, H interaction of CXCL10⁺ CCL19⁺ fibroblasts with T cells, I pro-inflammatory cytokine secretion and auto-amplification of CXCL10 production by CD4⁺ T cells, J actions mediated by posttranslationally modified IFN-inducible CXCR3 ligands generated after processing by synovial enzymes, K interaction with ACKR, and L angiostasis. How CXCL11 operates in the synovial microenvironment is less comprehended, as it may also reduce inflammation by outcompeting CXCL9/10 for CXCR3 and polarizing T_H cells towards T_r1 and T_H2 cells. ACKR atypical chemokine receptor, CCL CC chemokine receptor ligand, CCR CC chemokine receptor, CD13/APN metalloprotease aminopeptidase N, CD26/DPPIV dipeptidyl peptidase IV, CXCL CXC chemokine receptor ligand, CXCR CXC chemokine receptor, FLS fibroblast-like synoviocytes, GAG glycosaminoglycan, IL interleukin, MMP matrix metalloproteinase, pDC plasmacytoid DC, RANK Receptor activator of nuclear factor kappa-Β, RANKL RANKL Receptor activator of nuclear factor kappa-Β ligand, TLR4 Toll-like receptor 4, TNF-α tumor necrosis factor α, TRAP tartrate-resistant acid phosphatase