Reactive oxygen species regulate early development of the intestinal macrophage-microbiome interface

Mansoori Moghadam Z, Zhao B, Raynaud C, Strohmeier V, Neuber J, Lösslein AK, Qureshi S, Gres V, Ziegelbauer T, Baasch S, Schell C, Warnatz K, Inohara N, Nuñez G, Clavel T, Rosshart SP, Kolter J, Henneke P (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Blood American Society of Hematology

DOI: 10.1182/blood.2024025240

Abstract

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 p47^phox or gp91^phox showed similar baseline disturbances in lamina propria macrophage differentiation but responded differently to chemically induced colitis. Although p47^phox- and gp91^phox-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.

Authors with CRIS profile

Stephan Patrick Rosshart Professur für Mikrobiomik

Involved external institutions

Albert-Ludwigs-Universität Freiburg

Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen

Germany (DE) Universitätsklinikum Freiburg

Germany (DE) University of Michigan

United States (USA) (US)

How to cite

APA:

Mansoori Moghadam, Z., Zhao, B., Raynaud, C., Strohmeier, V., Neuber, J., Lösslein, A.K.,... Henneke, P. (2025). Reactive oxygen species regulate early development of the intestinal macrophage-microbiome interface. Blood. https://doi.org/10.1182/blood.2024025240

MLA:

Mansoori Moghadam, Zohreh, et al. "Reactive oxygen species regulate early development of the intestinal macrophage-microbiome interface." Blood (2025).

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