Functions of interleukin-34 and its emerging association with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic, synovial inflammation affecting multiple joints, finally leading to extra-articular lesions for which limited effective treatment options are currently available. Interleukin-34 (IL-34), recently discovered as the second colony-stimulating factor-1 receptor (CSF-1R) ligand, is a newly discovered cytokine. Accumulating evidence has disclosed crucial roles of IL-34 in the proliferation and differentiation of mononuclear phagocyte lineage cells, osteoclastogenesis and inflammation. Recently, IL-34 was detected at high levels in patients with active RA and in experimental models of inflammatory arthritis. Blockade of functional IL-34 with a specific monoclonal antibody can reduce the severity of inflammatory arthritis, suggesting that targeting IL-34 or its receptors may constitute a novel therapeutic strategy for autoimmune diseases such as RA. Here, we have comprehensively discussed the structure and biological functions of IL-34, and reviewed recent advances in our understanding of the emerging role of IL-34 in the development of RA as well as its potential utility as a therapeutic target.

Keywords: autoimmune; cytokine; inflammation; interleukin-34; rheumatoid arthritis.

Figure 1

Schematic structure of interleukin‐34 (IL‐34). A predicted N‐linked glycosylation site is indicated with an arrow symbol. Disulphide bridges are shown as solid purple line lines.

Figure 2

Structure of interleukin‐34 (IL‐34)/ colony‐stimulating factor‐1 receptor (CSF‐1R) complexes and the role of IL‐34/CSF‐1R in regulation of downstream signalling pathways. IL‐34 binds to the interdomain flexibly between D2 and D3 module of CSF‐1R. Signalling pathways, including extracellular signal‐regulated kinase 1/2 (ERK1/2), AKT, focal adhesion kinase (FAK), and signal transducer and activator of transcription 3 (STAT3) are rapidly activated, which subsequently regulate target gene expression and function in cell differentiation, proliferation, inflammation and immune responses. TFBS, transcription factor‐binding sites; VEGF, vascular endothelial growth factor.

Figure 3

Role of interleukin‐34 (IL‐34) in the pathological process of rheumatoid arthritis. IL‐34 acts through downstream mediators to exert biological effects on destruction of cartilage and bone and joint inflammation in rheumatoid arthritis.