IL13Rα1 protects against rheumatoid arthritis by combating the apoptotic resistance of fibroblast-like synoviocytes

Background Endoplasmic reticulum (ER) stress is closely related with the pathological progression of rheumatoid arthritis (RA), and fibroblast-like synoviocytes (FLSs) are known as its resistance against ER stress-induced apoptosis. Studies on overcoming such resistance would provide a novel treatment strategy for RA in a clinical setting. Methods IL13R alpha 1 expression was assessed in the synovial tissue by RT-qPCR, immunohistology, and Western blot. Gain or loss of functional analysis was applied to evaluate the biological roles of IL13R alpha 1 in RA FLSs. Cell viability and apoptosis were assessed by MTS, Western blot, and flow cytometry. The therapeutic effects of IL13R alpha 1 on the severity of type II collagen-induced arthritis (CIA) in DBA-/1 mouse model were evaluated by scoring synovitis, hyperplasia, cartilage degradation, and bone destruction. Results IL13R alpha 1 expression was selectively downregulated when RA FLSs were stimulated by ER stress inducers. Functionally, IL13R alpha 1 overexpression could inhibit the viability, but induce the apoptosis of RA FLSs in the presence of ER stress inducers. Mechanistically, IL13R alpha 1 promotes cell apoptosis via transcriptionally activating trail expression. Besides, IL13R alpha 1 could interact and stabilize DR5 protein, thus forming a positive loop involving trail and DR5 to render RA FLSs more susceptible to apoptosis. Additionally, intraarticular injection of IL13R alpha 1 conferred therapeutic effects in CIA models and showed a limited degree of synovial proliferation and joint destruction. Conclusions Together, our data establishes a regulatory role for IL13R alpha 1 to combat the apoptotic resistance of RA FLSs against ER stress. The inhibitory effects of IL13R alpha 1 on arthritis progression suggest the therapeutic potential in RA.