Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells

Abstract

AbstractCenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti‐HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2+/CCR5+ monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2+ and CCR5+ CD4+ T cells are enriched. Considering the role of CCR2+ and CCR5+ T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1‐, Th2‐, and Th17‐cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL‐10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up‐regulating the signature of Tr1 cell transcription factors such as c‐Maf, Prdm1, Irf‐1, Batf, and EGR‐2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL‐10 and inhibited the generation of pro‐inflammatory cytokines IFN‐γ, IL‐17, IL‐6, and IL‐1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti‐inflammatory Tr1 cells.