Figure 1.

Therapeutic targets related to monocyte and macrophage activation in juvenile idiopathic arthritis. Monocytes (Mos) were recruited to the joints by CCL2 and differentiated into tissue macrophages (Mφs) under inflammatory conditions. IL-1β, TNFα, IFNγ, GM-CSF, and IL-10 are especially important for the differentiation process. Upon stimulation with cytokines, immunocomplexes, TLR ligands, the hypoxic microenvironment, and microRNAs, the mixed polarization of Mφs toward an inflammatory phenotype was mediated via the JAK-STAT, MAPK, NFκB, TRIF, and HIF signaling pathways. Proinflammatory cytokines, including IL-1β, IL-6, IL-12, IL-18, IL-23, and TNFα were secreted to stimulate activation of osteoclasts and synovial fibroblasts and to promote T lymphocyte polarization. VEGF drives synovial angiogenesis, contributing to JIA pathogenesis. Available therapeutic targets are marked with red asterisks *. Abbreviations: RF, rheumatoid factor; ACPAs, anti-citrullinated protein antibodies; CCL2, monocyte chemoattractant protein 1; TLRs, Toll-like receptors; FcγR, Fc gamma receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; MAPKs, mitogen-activated protein kinases; TRIF, TIR-domain-containing adapter-inducing interferon; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; HIF, hypoxia-inducible factor; Th1, type 1 T helper cells; Th17, type 17 T helper cells; RANKL, receptor activator of nuclear factor kappa beta ligand.