Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production

William Becker; Haider Rasheed Alrafas; Kiesha Wilson; Kathryn Miranda; Courtney Culpepper; Ioulia Chatzistamou; Guoshuai Cai; Mitzi Nagarkatti; Prakash S Nagarkatti

doi:10.1016/j.isci.2020.101504

Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production

iScience. 2020 Aug 27;23(9):101504. doi: 10.1016/j.isci.2020.101504. eCollection 2020 Sep 25.

Authors

William Becker¹, Haider Rasheed Alrafas¹, Kiesha Wilson¹, Kathryn Miranda¹, Courtney Culpepper¹, Ioulia Chatzistamou¹, Guoshuai Cai², Mitzi Nagarkatti¹, Prakash S Nagarkatti¹

Affiliations

¹ Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
² Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.

Abstract

Intestinal disequilibrium leads to inflammatory bowel disease (IBD), and chronic inflammation predisposes to oncogenesis. Antigen-presenting dendritic cells (DCs) and macrophages can tip the equilibrium toward tolerance or pathology. Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40. Working through cannabinoid receptor 2 (CB2), THC increases CD103 expression on DCs and macrophages and upregulates TGF-β1 to increase T regulatory cells (Tregs). THC-induced Tregs are necessary to remedy systemic IFNγ and TNFα caused by anti-CD40, but CB2-mediated suppression of APCs by THC quenches pathogenic release of IL-22 and IL-17A in the colon. By examining tissues from multiple sites, we confirmed that THC affects DCs, especially in mucosal barrier sites in the colon and lungs, to reduce DC CD86. Using models of colitis and systemic inflammation we show that THC, through CB2, is a potent suppressor of aberrant immune responses by provoking coordination between APCs and Tregs.

Keywords: Cancer; Immunology.