A type 1 immune-stromal cell network mediates disease tolerance and barrier protection against intestinal infection

Susan Westfall, Maria E Gentile, Tayla M Olsen, Danielle Karo-Atar, Andrei Bogza, Franziska Roestel, Ryan Pardy, Giordano Mandato, Ghislaine Fontes, DeBroski Herbert, Heather J Melichar, Valerie Abadie, Martin Richer, Donald C Vinh, Joshua FE Koenig, Oliver J Harrison, Maziar J Divangahi, Sebastian Weis, Alex Gregorieff, Irah L King
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Abstract

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here we demonstrate that rapid induction of IFNg signaling coordinates a multi-cellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNg production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNg acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNg sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response had limited impact on parasite burden, indicating that IFNg supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodelling.
1 型免疫间质细胞网络介导疾病耐受和肠道感染屏障保护
1型免疫通过消灭病原体来介导宿主防御,但这种途径是否也会影响组织功能尚不清楚。在这里,我们证明了 IFNg 信号的快速诱导协调了多细胞反应,这对限制组织损伤和维持小鼠感染组织侵入性蠕虫后的肠道蠕动至关重要。在蠕虫诱导的屏障入侵过程中,固有层 CD8+ T 细胞依赖 MyD88 识别微生物群后,IFNg 在抗原无关的情况下被激活。IFNg 直接作用于肠道基质细胞,招募中性粒细胞,从而限制寄生虫诱导的组织损伤。IFNg 的感应还限制了平滑肌肌动蛋白表达细胞的扩张,从而防止了病理性肠道运动障碍。重要的是,这种组织保护反应对寄生虫负担的影响有限,这表明 IFNg 支持一种疾病耐受性防御策略。我们的研究结果对控制感染后肠道功能障碍的病理生理后遗症以及与基质重塑相关的慢性炎症性疾病具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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