Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Int Immunol. 2022 Jul 4;34(7):343-352. doi: 10.1093/intimm/dxac010.
CX3CR1high myeloid cells in the small intestine mediate the induction of oral tolerance by driving regulatory T (Treg) cells. Bacterial metabolites, e.g. pyruvate and lactate, induce a dendrite extension of CX3CR1high myeloid cells into the intestinal lumen via GPR31. However, it remains unclear whether the pyruvate-GPR31 axis is involved in the induction of oral tolerance. Here, we show that pyruvate enhances oral tolerance in a GPR31-dependent manner. In ovalbumin (OVA)-fed Gpr31-deficient mice, an OVA-induced delayed-type hypersensitivity response was substantially induced, demonstrating the defective induction of oral tolerance in Gpr31-deficient mice. The percentage of RORγt+ Treg cells in the small intestine was reduced in Gpr31-deficient mice. In pyruvate-treated wild-type mice, a low dose of OVA efficiently induced oral tolerance. IL-10 production from intestinal CX3CR1high myeloid cells was increased by OVA ingestion in wild-type mice, but not in Gpr31-deficient mice. CX3CR1high myeloid cell-specific IL-10-deficient mice showed a defective induction of oral tolerance to OVA and a decreased accumulation of OVA-specific Treg cells in the small intestine. These findings demonstrate that pyruvate enhances oral tolerance through a GPR31-dependent effect on intestinal CX3CR1high myeloid cells.
肠道中 CX3CR1 高表达的髓系细胞通过驱动调节性 T（Treg）细胞来介导口服耐受的诱导。细菌代谢产物，如丙酮酸和乳酸，通过 GPR31 诱导 CX3CR1 高表达的髓系细胞的树突延伸进入肠腔。然而，丙酮酸-GPR31 轴是否参与口服耐受的诱导仍不清楚。在这里，我们表明丙酮酸以 GPR31 依赖的方式增强口服耐受。在卵清蛋白（OVA）喂养的 Gpr31 缺陷小鼠中，OVA 诱导的迟发型超敏反应显著诱导，表明 Gpr31 缺陷小鼠中口服耐受的诱导受损。Gpr31 缺陷小鼠小肠中 RORγt+Treg 细胞的比例减少。在丙酮酸处理的野生型小鼠中，低剂量的 OVA 可有效诱导口服耐受。在野生型小鼠中，肠 CX3CR1 高表达的髓系细胞中 IL-10 的产生在摄入 OVA 后增加，但在 Gpr31 缺陷小鼠中则没有。CX3CR1 高表达的髓系细胞特异性 IL-10 缺陷小鼠对 OVA 的口服耐受诱导受损，并且在小肠中 OVA 特异性 Treg 细胞的积累减少。这些发现表明，丙酮酸通过对肠道 CX3CR1 高表达的髓系细胞的 GPR31 依赖性作用增强口服耐受。
