Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan;
The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan.
Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):8418-8423. doi: 10.1073/pnas.1808426115. Epub 2018 Jul 30.
The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CXCR1 Mϕs. Intestinal CXCR1 Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific -deficient (; ) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CXCR1 Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from ; mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the and promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the noninflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.
局部环境对于组织驻留巨噬细胞 (Mϕ) 的表型形成至关重要。当受损组织发生出血时，血红蛋白诱导具有修复功能的抗炎 Mϕ 分化。黏膜出血是炎症性肠病的病理特征之一。然而，血红素介导的调节肠道固有免疫细胞激活的机制仍知之甚少。在这里，我们表明血红素通过诱导肠道 CXCR1 Mϕ 中的 Spi-C 来调节肠道稳态。肠道 CXCR1 Mϕ 以血红素依赖的方式高度表达 Spi-C，髓系特异性缺失 Spi-C 的小鼠（; ）在葡聚糖硫酸钠诱导的结肠炎中表现出严重的肠道炎症，Th17 细胞数量增加。Spi-C 下调肠道 CXCR1 Mϕ 中一组 Toll 样受体 (TLR) 诱导基因的表达，以预防结肠炎。LPS 诱导的来自 ; 小鼠的大肠 Mϕ 产生的 IL-6 和 IL-1α，但不是 IL-10 和 TNF-α，明显增强。Spi-C 与 IRF5 的相互作用与破坏 IRF5-NF-κB p65 复合物的形成有关，从而阻止了 IRF5 和 NF-κB p65 募集到 和 启动子。总之，这些结果表明，血红素介导的 Spi-C 是肠道 Mϕ 非炎症表型的关键分子，通过与 IRF5 结合抑制一组 TLR 诱导基因的诱导来实现。
