Mansoori Moghadam Zohreh, Zhao Bei, Raynaud Candice, Strohmeier Valentina, Neuber Jana, Lösslein Anne Kathrin, Qureshi Sabrina, Gres Vitka, Ziegelbauer Tara, Baasch Sebastian, Schell Christoph, Warnatz Klaus, Inohara Naohiro, Nuñez Gabriel, Clavel Thomas, Rosshart Stephan P, Kolter Julia, Henneke Philipp
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute for Infection Control and Prevention, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Blood. 2025 May 1;145(18):2025-2040. doi: 10.1182/blood.2024025240.
The controlled development of cellular intestinal immunity in the face of dynamic microbiota emergence constitutes a major challenge in very early life and is a bottleneck for sustained growth and well-being. Early-onset inflammatory bowel disease (IBD) represents an extreme disturbance of intestinal immunity. It is a hallmark and often the first manifestation of chronic granulomatous disease (CGD), caused by inborn defects in the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) in phagocytes and thus the failure to produce reactive oxygen species (ROS). However, in contrast to the known role of ROS in antimicrobial defense, the mechanisms underlying intestinal immunopathology in CGD remain enigmatic. This is partly due to the incomplete recapitulation of the CGD-IBD phenotype in established mouse models. We found that mice deficient in the NOX2 subunits p47phox or gp91phox showed similar baseline disturbances in lamina propria macrophage differentiation but responded differently to chemically induced colitis. Although p47phox- and gp91phox-deficient mice differed markedly in microbiota composition, crossfostering failed to equalize discrepant IBD phenotypes and microbiota, pointing at extremely early and functionally important microbiota fixation under specific pathogen-free housing conditions. In contrast, neonatal acquisition of a complex wild-mouse microbiota triggered spontaneous IBD, granuloma formation, and secondary sepsis with intestinal pathogens in both NOX2-deficient mouse lines, which was in part dependent on NOX2 in intestinal macrophages. Thus, in experimental CGD, the aberrant development of tissue immunity and microbiota are closely intertwined immediately after birth.
面对动态出现的微生物群，细胞性肠道免疫的可控发展是生命早期的一项重大挑战，也是持续生长和健康的一个瓶颈。早发性炎症性肠病（IBD）代表了肠道免疫的极端紊乱。它是慢性肉芽肿病（CGD）的一个标志，且往往是其首发表现，CGD由吞噬细胞中烟酰胺腺嘌呤二核苷酸磷酸氧化酶2（NOX2）的先天性缺陷引起，进而导致无法产生活性氧（ROS）。然而，与ROS在抗菌防御中的已知作用相反，CGD中肠道免疫病理学的潜在机制仍然不明。部分原因是在已建立的小鼠模型中CGD - IBD表型的不完全重现。我们发现，缺乏NOX2亚基p47phox或gp91phox的小鼠在固有层巨噬细胞分化方面表现出相似的基线紊乱，但对化学诱导的结肠炎反应不同。尽管p47phox缺陷型和gp91phox缺陷型小鼠的微生物群组成存在显著差异，但交叉寄养未能使不一致的IBD表型和微生物群达到平衡，这表明在特定病原体-free饲养条件下，微生物群在极早期就已固定且具有重要功能。相比之下，新生小鼠获得复杂的野生小鼠微生物群会引发两种NOX2缺陷型小鼠品系的自发性IBD、肉芽肿形成以及肠道病原体继发败血症，这部分依赖于肠道巨噬细胞中的NOX2。因此，在实验性CGD中，出生后组织免疫和微生物群的异常发育立即紧密交织在一起。
