Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY.
Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA.
J Exp Med. 2019 Jun 3;216(6):1268-1279. doi: 10.1084/jem.20180131. Epub 2019 Apr 11.
Type 2 inflammation drives the clearance of gastrointestinal helminth parasites, which infect over two billion people worldwide. Basophils are innate immune cells that support host-protective type 2 inflammation during murine infection with the helminth However, the mechanisms required for basophil function and gene expression regulation in this context remain unclear. We show that during infection, basophils localized to the intestine and up-regulated Notch receptor expression, rendering them sensitive to Notch signals that rapidly regulate gene expression programs. In vitro, Notch inhibition limited basophil cytokine production in response to cytokine stimulation. Basophil-intrinsic Notch signaling was required for -elicited changes in genome-wide basophil transcriptional programs. Mice lacking basophil-intrinsic functional Notch signaling had impaired worm clearance, decreased intestinal type 2 inflammation, altered basophil localization in the intestine, and decreased CD4 T helper 2 cell responses following infection. These findings demonstrate that Notch is required for basophil gene expression and effector function associated with helminth expulsion during type 2 inflammation.
2 型炎症可清除全球超过 20 亿人感染的胃肠道寄生虫。嗜碱性粒细胞是先天免疫细胞，在感染蠕虫时支持宿主保护性的 2 型炎症。然而，在这种情况下，嗜碱性粒细胞功能和基因表达调控所需的机制仍不清楚。我们发现，在感染过程中，嗜碱性粒细胞定位于肠道并上调 Notch 受体表达，使其对 Notch 信号敏感，而 Notch 信号可快速调节基因表达程序。在体外，Notch 抑制限制了嗜碱性粒细胞对细胞因子刺激的细胞因子产生。嗜碱性粒细胞固有 Notch 信号对于诱导的全基因组嗜碱性粒细胞转录程序变化是必需的。缺乏嗜碱性粒细胞固有功能性 Notch 信号的小鼠在感染后清除蠕虫的能力受损，肠道 2 型炎症减少，肠道中嗜碱性粒细胞定位改变，CD4 T 辅助 2 细胞反应减少。这些发现表明，Notch 对于与 2 型炎症期间寄生虫排出相关的嗜碱性粒细胞基因表达和效应功能是必需的。
