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

Eur J Immunol. 2024 Jul;54(7):e2350847. doi: 10.1002/eji.202350847. Epub 2024 Apr 21.

Abstract

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.

Keywords: Autoimmunity; CD4 T cells; Cell differentiation; Inflammation; Regulatory T cells.

MeSH terms

  • Animals
  • CCR5 Receptor Antagonists* / pharmacology
  • CCR5 Receptor Antagonists* / therapeutic use
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / immunology
  • Colitis* / chemically induced
  • Colitis* / drug therapy
  • Colitis* / immunology
  • Humans
  • Imidazoles
  • Interleukin-10 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CCR2* / antagonists & inhibitors
  • Receptors, CCR2* / metabolism
  • Receptors, CCR5* / metabolism
  • Sulfoxides / pharmacology
  • T-Lymphocytes, Regulatory* / drug effects
  • T-Lymphocytes, Regulatory* / immunology
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Th2 Cells / immunology

Substances

  • cenicriviroc
  • Receptors, CCR2
  • CCR5 Receptor Antagonists
  • Receptors, CCR5
  • Sulfoxides
  • Ccr2 protein, mouse
  • CCR5 protein, mouse
  • Interleukin-10
  • Imidazoles