Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America.
PLoS One. 2011 Apr 1;6(4):e18281. doi: 10.1371/journal.pone.0018281.
Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.
METHODOLOGY/PRINCIPAL FINDINGS: Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.
CONCLUSIONS/SIGNIFICANCE: This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases.
髓系来源的抑制细胞（MDSCs）作为免疫系统的主要调节细胞之一，越来越受到关注。它们在炎症部位诱导产生，并能有效地抑制 T 细胞功能。在本研究中，我们证明了 TRPV1 香草素受体的激活如何触发 MDSCs，反过来，又可以抑制炎症和肝炎。
方法/主要发现：在 C57BL/6 小鼠中，注射刀豆蛋白 A（ConA）后多克隆激活 T 细胞会导致急性肝炎，其特征是天冬氨酸转氨酶（AST）显著升高、诱导炎症细胞因子、单核细胞浸润肝脏，导致严重的肝损伤。大麻二酚（CBD），一种天然的非精神活性大麻素，在 ConA 挑战后给药，以剂量依赖的方式抑制肝炎，同时抑制所有相关的炎症标志物。对肝脏浸润细胞的表型分析表明，CBD 介导的肝炎抑制与诱导表达精氨酸酶的 CD11b(+)Gr-1(+)MDSCs 的增加有关。CBD 诱导的 MDSCs 可以有效地在体外以依赖精氨酸酶的方式抑制 T 细胞增殖。此外，将纯化的 MDSCs 过继转移到 naive 小鼠中，可显著防止 ConA 诱导的肝炎。CBD 未能在香草素受体缺陷型小鼠（TRPV1(-/-)）的肝脏中诱导 MDSCs 并抑制肝炎，从而表明 CBD 主要通过该受体诱导 MDSCs 并抑制肝炎。虽然 CBD 在肝脏中诱导的 MDSCs 由粒细胞和单核细胞亚群组成，比例约为 2∶1，但与粒细胞 MDSCs 相比，单核 MDSCs 具有更强的免疫抑制作用。CBD 诱导 MDSCs 和抑制由葡萄球菌肠毒素 B 诱导的肝损伤中的肝炎的能力也得到了证明。
结论/意义：本研究首次证明 MDSCs 在减轻肝脏急性炎症中起关键作用，并且像 CBD 这样的药物，通过激活 TRPV1 香草素受体来触发 MDSCs，可能构成治疗炎症性疾病的一种新的治疗模式。
