正常的巨噬细胞激活和胃幽门螺杆菌免疫需要内源性糖皮质激素
Endogenous glucocorticoids are required for normal macrophage activation and gastric Helicobacter pylori immunity
影响因子:3.30000
分区:医学3区 / 生理学2区 胃肠肝病学3区
发表日期:2024 Oct 01
作者:
Stuti Khadka, Sebastian A Dziadowicz, Xiaojiang Xu, Lei Wang, Gangqing Hu, Javier A Carrero, Richard J DiPaolo, Jonathan T Busada
摘要
糖皮质激素是类固醇激素，以其有效的抗炎作用而闻名。但是，它们的免疫调节特性是多方面的。越来越多的证据表明，糖皮质激素信号传导促进有效的免疫力，并且糖皮质激素信号的破坏会损害免疫功能。在这项研究中，我们使用LYSM-CRE驱动器（MyGrko）有条件地删除了髓样谱系中的糖皮质激素受体（GR）。我们检查了对巨噬细胞激活和胃免疫反应对幽门螺杆菌的影响，幽门螺杆菌是胃癌的最著名危险因素。我们的结果表明，与野生型（WT）相比，糖皮质激素受体敲除（GRKO）巨噬细胞在无类固醇条件下表现出促炎基因的较高表达。但是，当受到挑战的体内挑战时，Grko巨噬细胞表现出异常的染色质景观和促炎性基因表达谱。此外，幽门螺杆菌胃定植揭示了胃免疫反应受损并减少了Mygrko小鼠的T细胞募集。结果，mygrko小鼠免受萎缩性胃炎和幽门化的化学发育的保护。这些结果表明，糖皮质激素信号传导在制备巨噬细胞以应对细菌感染中的双重作用，但限制了它们的致病激活。此外，我们的结果支持巨噬细胞对胃h.幽门杆菌免疫至关重要。
Abstract
Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity.NEW & NOTEWORTHY Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection.