IRE1α-Driven Inflammation Promotes Clearance of Citrobacter rodentium Infection.
IRE1α-Driven Inflammation Promotes Clearance of Citrobacter rodentium Infection.
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DOI：
10.1128/iai.00481-21
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发表时间：
2022-01-25
影响因子：
3.1
通讯作者：
Keestra-Gounder AM
中科院分区：
文献类型：
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作者：
Sweet LA;Kuss-Duerkop SK;Keestra-Gounder AM
内质网（ER）应激与病原性感染引起的炎症反应密切相关。当细胞在扰动期间（如感染）经历错误折叠或未折叠蛋白质的积累时，会发生ER应激，这有助于未折叠蛋白质反应（UPR）。UPR涉及多个宿主途径，试图重建稳态，如果未解决，这通常会导致炎症和细胞死亡。UPR被激活以帮助解决一些细菌感染，IRE 1 α通路在介导炎症中尤其重要。为了了解UPR的IRE 1 α途径在肠道细菌感染中的作用，我们采用啮齿类柠檬酸杆菌研究肠上皮细胞和小鼠胃肠道（GI）中的宿主-病原体相互作用。C.啮齿类是一种小鼠肠道病原体，与人类病原体肠致病性和肠出血性大肠杆菌（分别为EPEC和EHEC）相似，我们对它们的小动物模型有限。在这里，我们证明了这两个C。啮齿类和EPEC诱导肠上皮细胞UPR。在C.啮齿类感染与骨髓源性巨噬细胞（BMDM）炎症的发生相关。我们以前的工作表明，IRE 1 α和NOD 1/2参与了ER应激诱导的炎症反应，我们观察到它们也是C.啮齿类感染C.在小鼠中，啮齿类动物诱导IRE 1 α依赖性炎症，抑制IRE 1 α导致炎症反应失调和C.啮齿动物。这项研究表明，ER应激有助于炎症和C。啮齿类通过涉及IRE 1 α-NOD 1/2轴的机制。
Endoplasmic reticulum (ER) stress is intimately linked with inflammation in response to pathogenic infections. ER stress occurs when cells experience a buildup of misfolded or unfolded protein during times of perturbation, such as infections, which facilitates the unfolded protein response (UPR). The UPR involves multiple host pathways in an attempt to reestablish homeostasis, which oftentimes leads to inflammation and cell death if unresolved. The UPR is activated to help resolve some bacterial infections, and the IRE1α pathway is especially critical in mediating inflammation. To understand the role of the IRE1α pathway of the UPR during enteric bacterial infection, we employed Citrobacter rodentium to study host-pathogen interactions in intestinal epithelial cells and the murine gastrointestinal (GI) tract. C. rodentium is an enteric mouse pathogen that is similar to the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), for which we have limited small-animal models. Here, we demonstrate that both C. rodentium and EPEC induced the UPR in intestinal epithelial cells. UPR induction during C. rodentium infection correlated with the onset of inflammation in bone marrow-derived macrophages (BMDMs). Our previous work implicated IRE1α and NOD1/2 in ER stress-induced inflammation, which we observed were also required for proinflammatory gene induction during C. rodentium infection. C. rodentium induced IRE1α-dependent inflammation in mice, and inhibiting IRE1α led to a dysregulated inflammatory response and delayed clearance of C. rodentium. This study demonstrates that ER stress aids inflammation and clearance of C. rodentium through a mechanism involving the IRE1α-NOD1/2 axis.