A reappraisal of the contribution of Th9 cells and interleukin-9 to the pathogenesis of rheumatoid arthritis.

Interleukin-9 (IL-9), the principal cytokine of Th9 cells, influences a vast range of functions due to the widespread expression of its receptor on various immune and non-immune cell types. Th9 cells and IL-9 play a detrimental role in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis (RA). Elevated Th9 cell numbers and higher IL-9 levels were observed in the peripheral blood and synovial tissues of patients with RA and animals with collagen-induced arthritis (CIA), correlating with disease activity. IL-9 can contribute to the pathogenesis of RA through multiple mechanisms, such as promoting the expansion and survival of pathogenic T cells; impairing the activity of regulatory T (Treg) cells; boosting the pathogenic responses of Th1 and Th17 cells; prolonging the survival and increasing the activity of synovial neutrophils; supporting the differentiation and activation of osteoclasts; enhancing the proliferation and survival of fibroblast-like synoviocytes (FLS); inducing the secretion of pro-inflammatory mediators from FLS; facilitating the polarization of pro-inflammatory M1 macrophages; and promoting the expansion of Th9 cells. Experimental and clinical evidence suggests that targeting IL-9/IL-9R and Th9 cells may be a promising approach for RA treatment. In addition, treatment with mesenchymal stem cells and various therapeutic agents showed beneficial effects in RA by downregulating inflammatory responses, such as Th9 cells and IL-9. This review provides a comprehensive explanation regarding the role of Th9 cells/IL-9 in RA pathogenesis and potential therapeutic approaches based on experimental and clinical findings.