内源性糖皮质激素对正常巨噬细胞活化和胃幽门螺杆菌免疫的必要性

Endogenous glucocorticoids are required for normal macrophage activation and gastric Helicobacter pylori immunity

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

影响因子:3.3

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

DOI: 10.1152/ajpgi.00114.2024

摘要

糖皮质激素是众所周知具有强大抗炎作用的类固醇激素，但其免疫调节特性复杂多样。越来越多的证据表明，糖皮质激素信号促进有效免疫反应，干扰糖皮质激素信号会削弱免疫功能。本研究中，我们使用LysM-Cre驱动基因敲除技术（myGRKO）条件性删除了髓系细胞中的糖皮质激素受体（GR）。我们观察了其对巨噬细胞激活以及对胃部抗幽门螺杆菌免疫应答的影响，幽门螺杆菌是已知的胃癌主要风险因素。结果显示，与野生型（WT）相比，无糖皮质激素受体（GRKO）巨噬细胞在无激素条件下表现出更高的促炎基因表达。然而，在体内受到挑战时，GRKO巨噬细胞显示出异常的染色质结构和受损的促炎基因表达谱。此外，感染幽门螺杆菌的胃部发现，GRKO小鼠的免疫反应受损，T细胞募集减少。因此，myGRKO小鼠能避免萎缩性胃炎和幽门腺化的发生。这些结果表明，糖皮质激素信号在准备巨噬细胞应对细菌感染方面具有双重作用——既促使其反应，也限制其致病性激活。此外，我们的研究还支持巨噬细胞在幽门螺杆菌免疫中起关键作用。新颖且值得注意的是：内源性糖皮质激素的信号调节能增强巨噬细胞对病原体的反应。干扰糖皮质激素信号会导致染色质结构失调，削弱细菌挑战时的促炎基因激活，进而影响胃部对幽门螺杆菌感染的炎症反应。

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.