降低 IRF5 表达可减轻小鼠的结肠炎，但会损害肠道病原体的清除。,Mucosal Immunology

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降低 IRF5 表达可减轻小鼠的结肠炎，但会损害肠道病原体的清除。
Mucosal Immunology ( IF 7.9 ) Pub Date : 2019-05-03 , DOI: 10.1038/s41385-019-0165-1
Surya P Pandey ₁ , Jie Yan ₁ , Jerrold R Turner ₂ , Clara Abraham ₁

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导致 IRF5 表达降低的 IRF5 遗传变异可降低溃疡性结肠炎的风险。然而，IRF5 如何调节肠道炎症并有助于在体内抵御肠道病原体和炎症之间的平衡，以及介导这种平衡的细胞尚不清楚。我们发现在小鼠中删除 IRF5 会导致 T 细胞转移结肠炎模型中的肠道炎症减少，Th1 和 Th17 减少，Th2 细胞因子增加。然而，对于口服侵入性鼠伤寒沙门氏菌，IRF5-/-小鼠在 Th1 和 Th17 细胞因子减少的情况下表现出细菌负荷增加。PDK1 依赖性吞噬作用和 NFκB 依赖性通路介导细胞内细菌清除需要巨噬细胞中的 IRF5。尽管减少了细菌清除途径，在 DSS 诱导损伤后暴露于高水平常驻肠道细菌的 IRF5-/- 小鼠中，较低水平的炎症细胞因子与肠道通透性降低相关，进而减少细菌移位和肠道炎症。与体外 IRF5 的骨髓细胞内在作用一致，从骨髓细胞中删除 IRF5 的小鼠表现出与在 IRF5-/- 小鼠中观察到的相似的结果。虽然这些数据表明抑制 IRF5 可能对结肠炎有治疗作用，但这需要与已确定的 IRF5 在抵御肠道病原体方面的作用相平衡。与体外 IRF5 的骨髓细胞内在作用一致，从骨髓细胞中删除 IRF5 的小鼠表现出与在 IRF5-/- 小鼠中观察到的相似的结果。虽然这些数据表明抑制 IRF5 可能对结肠炎有治疗作用，但这需要与已确定的 IRF5 在抵御肠道病原体方面的作用相平衡。与体外 IRF5 的骨髓细胞内在作用一致，从骨髓细胞中删除 IRF5 的小鼠表现出与在 IRF5-/- 小鼠中观察到的相似的结果。虽然这些数据表明抑制 IRF5 可能对结肠炎有治疗作用，但这需要与已确定的 IRF5 在抵御肠道病原体方面的作用相平衡。

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Reducing IRF5 expression attenuates colitis in mice, but impairs the clearance of intestinal pathogens.

IRF5 genetic variants leading to decreased IRF5 expression reduce risk for ulcerative colitis. However, how IRF5 regulates intestinal inflammation and contributes to the balance between defenses against intestinal pathogens and inflammation in vivo, and the cells mediating this balance, are not known. We found that deleting IRF5 in mice led to reduced intestinal inflammation in the T cell transfer colitis model, with reduced Th1 and Th17, and increased Th2 cytokines. However, with orally-administered invasive S. Typhimurium, IRF5-/- mice demonstrated an increased bacterial burden in the context of reduced Th1 and Th17 cytokines. IRF5 in macrophages was required for PDK1-dependent phagocytosis and for NFκB-dependent pathways mediating intracellular bacterial clearance. Despite reduced bacterial clearance pathways, in IRF5-/- mice exposed to high levels of resident intestinal bacteria after DSS-induced injury, the lower levels of inflammatory cytokines were associated with reduced intestinal permeability, and in turn, reduced bacterial translocation and intestinal inflammation. Consistent with the myeloid cell-intrinsic roles for IRF5 in vitro, mice with IRF5 deleted from myeloid cells demonstrated outcomes similar to those observed in IRF5-/- mice. While these data suggest that inhibition of IRF5 may be therapeutic in colitis, this needs to be balanced with the identified IRF5 role in protecting against intestinal pathogens.

更新日期：2019-05-16

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