Interleukin-34 Aggravates the Severity of Arthritis in Collagen-Induced Arthritis Mice by Inducing Interleukin-17 Production

Abstract

To explore the immunological mechanisms underlying the effect of exogenous interleukin-34 (IL-34) on collagen-induced arthritis (CIA) in mouse. We established a CIA mouse model and injected exogenous recombination mouse IL-34 (rmIL-34) intraperitoneally. The articular index (AI) was measured according to the amount of erythema, swelling, or joint rigidity. The concentrations of TNF-α, IL-17, and IL-6 in CIA mice sera were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of TNF-α, IL-17, and IL-6 in CIA synovial tissue were detected by reverse transcription PCR. The CIA mice dosed with rmIL-34 exhibited increased AI. Neutralization of endogenous IL-17 with anti-IL-17 antibody reduced the effect of IL-34. TNF-α, IL-17, and IL-6 levels in serum in IL-34-treated CIA mice were increased compared to those in CIA mice. IL-34 increased the expression of TNF-α and IL-17 mRNA in synovial tissues of CIA mice, but the gene expression of IL-6 was not affected. The effects of IL-34 on TNF-α, IL-17, and IL-6 expression were abolished by anti-IL-17 antibody. In conclusion, IL-34 acts as a proinflammatory factor, aggravating the severity of arthritis in CIA mice by inducing the production of IL-17.

Interleukin-34, a comprehensive review

“…Since IL‐34 is expressed at mRNA level in various tissues, this expression is expected to be changed under pathological conditions. Indeed, several studies have confirmed the enhancement of IL‐34 expression at mRNA and protein levels in the context of various diseases including autoimmune disorders, inflammation, infections, metabolic diseases, neurological disorders, and cancer . At the cellular level, IL‐34‐producing cells include synovial fibroblasts, immune cells, epithelial cells, endothelial cells, adipocytes, and cancer cells.…”

“…A) . Using the same model, IL‐34 was found to aggravate disease severity by enhancing levels of pro‐inflammatory cytokines such as IL‐6, IL‐17, and TNF‐α …”

“…In addition to clinical studies, several reports have also evaluated the expression of IL‐34 in experimental animal models. IL‐34 expression showed an enhancement in murine models of collagen‐ or Ab‐induced arthritis, Huntington's disease, dextran sulfate sodium‐induced colitis, kidney ischemia, systemic lupus erythematosus (SLE) nephritis, and sepsis . The expression of IL‐34 is also increased in infection models such as in SIV with encephalitis in rhesus macaques, Cryptocaryon irritans in grouper, Vibrio anguillarum in large yellow croaker, and in a fish‐parasite infection model ( Enteromyxum leei in Sparus aurata ) …”

“…Pro‐inflammatory cytokines are fundamental to the pathophysiology of RA. Numerous studies have unveiled the pathologic role of IL‐34 in RA as a downstream effector of pro‐inflammatory cytokines, contributing importantly to inflammation and bone erosion . Elevated levels of IL‐34 can be detected in the blood, synovial fluids, and synovial tissues of RA patients.…”

“…Evidence from in vitro experiments has shown that pro‐inflammatory cytokines, including TNF‐α, IL‐1β, IL‐6, and IL‐17, can induce the expression of IL‐34 in osteoblasts and synovial fibroblasts via JNK‐ and NF‐κB‐mediated mechanisms . Functionally, IL‐34 contributes to the pathophysiology of RA via multiple molecular and cellular mechanisms: (1) IL‐34 mediates a positive feedback loop that results in an enhanced expression of pro‐inflammatory cytokines such as IL‐6 and IL‐17, (2) promotes migration of PBMCs that showed enhanced expression of IL‐17, (3) enhances proliferation and differentiation of M ϕ s, which serve as a predominant infiltrating cell type in the inflamed synovia that promotes inflammation by enriching the environment with pro‐inflammatory factors, and (4) supports RANKL‐induced osteoclastogenesis resulting in bone erosions . Additionally, IL‐34 induces STAT3 activation and miRNA‐21 increment in synovial fibroblast, resulting in increased resistance of fibroblast to apoptosis and enhanced IL‐6 expression, which in turns contribute to Th17 production .…”