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

Cenicriviroc, 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.