A spontaneous arthritis mouse model driven by TNF-alpha overexpression

Rheumatoid arthritis (RA) is the most prevalent autoimmune arthropathy characterized by persistent inflammation, pain, swelling and progressive destruction of the synovial joints. Tumor necrosis factor alpha (TNFalpha) plays a central role in the autoimmune response leading to RA, as evidenced by the significant therapeutic benefits observed upon its inhibition. However, certain inhibitors targeting human TNFalpha (hTNFalpha), such as Infliximab, failed to cross-neutralize mouse TNFalpha (mTNFalpha). This limitation has impeded mechanistic and therapeutic investigations of hTNFalpha inhibitors in vivo , necessitating the development of humanized mouse models expressing hTNFalpha.Here, we developed an hTNFalpha transgenic mouse model (hTNFalpha-Tg) in C57BL/6 background, which carries the native promoter and coding sequences of the human TNFalpha gene, thereby driving robust overexpression of the human TNFalpha, as a relevant model for RA. By measuring serum hTNFalpha levels through ELISA following LPS stimulation, we confirmed significant overexpression of both hTNFalpha and endogenous mTNFalpha. Regarding the RA phenotype, macroscopic evaluation of arthritis revealed visible joint swelling in hTNFalpha-Tg mice compared to wild-type mice. Micro-CT imaging further confirmed prominent joint bone loss in hTNFalpha-Tg mice, validating their utility as an RA mouse model. To assess the in vivo therapeutic efficacy of hTNFalpha-targeted inhibitors, we administrated Infliximab to hTNFalpha-Tg mice and observed that Infliximab significantly reduced pathological scores of joint swelling and paw thickness, along with a significant increase in body weight gain. Concurrently, the treated mice exhibited amelioration of the joint space widening caused by bone destruction or inflammation, as well as phalangeal deformity.Overall, our hTNFalpha-Tg mouse model provides a powerful preclinical platform for the development of drugs targeting the hTNFalpha protein and for evaluating their efficacy and toxicity in vivo.