Abstract
Abstract Tissue transglutaminase (TG2) has a critical role in the pathogenesis of chronic inflammatory diseases. We have previously described the key role of TG2 in cystic fibrosis (CF), a genetic disease characterised by chronic lung infections and inflammation. In CF, mutation on the CFTR gene results in an increased TG2 expression and activity leading to functional sequestration of the anti-inflammatory PPARγ and increase of inflammation. Here we tested whether in vivo inhibition of TG2 can reverse inflammation in chronic inflammatory diseases. To assess the importance of TG2, we injected cystamine, a potent TG2 inhibitor, in a transgenic mouse model of CF and in the TAZ10 transgenic mice that spontaneously develop autoimmune thyroiditis. Intraperitoneal administration of cystamine had a significant impact on the lung epithelium in the CF model, where it decreased TG expression and activity. The treatment was also able to dampen all the classic inflammatory parameters as well as restoring normal cellular levels of functional PPARγ. Interestingly, cystamine injections could also block inflammation in the TAZ10 TCR transgenic mouse model, highlighting the pivotal role of TG2 in generating inflammation in two very different pathologies. This work underlines the critical role of TG2 in inflammation and provides new opportunities to develop therapeutic strategies for sufferers of chronic inflammatory diseases.