iScience ( IF 5.8 ) Pub Date : 2020-08-27 , DOI: 10.1016/j.isci.2020.101504 William Becker 1 , Haider Rasheed Alrafas 1 , Kiesha Wilson 1 , Kathryn Miranda 1 , Courtney Culpepper 1 , Ioulia Chatzistamou 1 , Guoshuai Cai 2 , Mitzi Nagarkatti 1 , Prakash S Nagarkatti 1
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.
中文翻译:
大麻素受体2的激活通过IL-22生产上游的髓样细胞失活防止结肠炎相关的结肠癌。
肠道失衡会导致炎症性肠病(IBD),而慢性炎症易致癌。呈递抗原的树突状细胞(DC)和巨噬细胞可使平衡趋向于耐受或病理。在这里,我们显示delta-9-tetrahydrocannabinol(THC)减弱了结肠炎相关的结肠癌和抗CD40诱导的结肠炎。THC通过大麻素受体2(CB2)起作用,从而增加DC和巨噬细胞上CD103的表达,并上调TGF-β1以增加T调节细胞(Tregs)。THC诱导的Tregs是补救由抗CD40引起的全身性IFNγ和TNFα所必需的,但是THC的CB2介导的APC抑制抑制了结肠中IL-22和IL-17A的致病性释放。通过检查多个部位的组织,我们确认四氢大麻酚会影响DC,尤其是结肠和肺的粘膜屏障部位,减少DC CD86。使用结肠炎和全身性炎症的模型,我们表明THC通过CB2通过激发APC和Treg之间的协调作用,有效抑制了异常的免疫反应。