Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner.
| Autor: | Chauvin C; Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France.; Institut national de la santé et de la recherche médicale (INSERM) U1138, Centre de Recherche des Cordeliers, Paris, France., Radulovic K; Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes, France., Boulard O; Univ. Lille, Inserm, U1003, Lille, France., Delacre M; Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France., Waldschmitt N; Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany., Régnier P; Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France.; Biotherapy Unit (CIC-BTi), Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France., Legris G; Univ. Lille, Inserm, U1003, Lille, France., Bouchez C; Univ. Lille, Inserm, U1003, Lille, France., Sleimi MY; Univ. Lille, Inserm, U1003, Lille, France., Rosenstiel P; Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany., Darrasse-Jèze G; Immunology-Immunopathology-Immunotherapy (i3) Laboratory, Institut national de la santé et de la recherche médicale (INSERM) UMR-S 959, Sorbonne Université, Paris, France.; Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France.; Université Paris Cité, Faculté de Médecine, Paris, France., Chamaillard M; Univ. Lille, Inserm, U1003, Lille, France., Poulin LF; Univ. Lille, Inserm, U1003, Lille, France. |
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| Jazyk: | angličtina |
| Zdroj: | Frontiers in immunology [Front Immunol] 2023 Oct 09; Vol. 14, pp. 1252979. Date of Electronic Publication: 2023 Oct 09 (Print Publication: 2023). |
| DOI: | 10.3389/fimmu.2023.1252979 |
| Abstrakt: | Background: Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the NOD2 gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC). Methods: To ablate Nod2 specifically within the myeloid compartment, we generated LysM Cre/+ ;Nod2 fl/fl mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis. Results: Upon DSS colitis model, LysM Cre/+ ;Nod2 fl/fl mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of LysM Cre/+ ;Nod2 fl/fl mice, associated with less expression of Tgfb . Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells. Conclusion: Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Chauvin, Radulovic, Boulard, Delacre, Waldschmitt, Régnier, Legris, Bouchez, Sleimi, Rosenstiel, Darrasse-Jèze, Chamaillard and Poulin.) |
| Databáze: | MEDLINE |
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