NOD2 in monocytes negatively regulates macrophage development through TNFalpha.

Autor:	Chauvin C; U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France.; INSERM U1138, Centre de Recherche des Cordeliers, Paris, France., Alvarez-Simon D; U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France., Radulovic K; Unité de Recherche Clinique, Centre Hospitalier de Valenciennes, Valenciennes CEDEX, France., Boulard O; U1003, Univ. Lille Inserm, Lille, France., Laine W; UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France., Delacre M; U1019, Institut Pasteur de Lille, Univ. Lille, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalo- Universitaire Lille, Lille, France., Waldschmitt N; Chair of Nutrition and Immunology, School of Life Sciences, Technische Universität München, Freising-Weihenstephan, Germany., Segura E; INSERM U932, Institut Curie, Paris Sciences et Lettres Research University, Paris, France., Kluza J; UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France., Chamaillard M; U1003, Univ. Lille Inserm, Lille, France., Poulin LF; U1003, Univ. Lille Inserm, Lille, France.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Jun 21; Vol. 14, pp. 1181823. Date of Electronic Publication: 2023 Jun 21 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1181823
Abstrakt:	Objective: It is believed that intestinal recruitment of monocytes from Crohn's Disease (CD) patients who carry NOD2 risk alleles may repeatedly give rise to recruitment of pathogenic macrophages. We investigated an alternative possibility that NOD2 may rather inhibit their differentiation from intravasating monocytes. Design: The monocyte fate decision was examined by using germ-free mice, mixed bone marrow chimeras and a culture system yielding macrophages and monocyte-derived dendritic cells (mo-DCs). Results: We observed a decrease in the frequency of mo-DCs in the colon of Nod2 -deficient mice, despite a similar abundance of monocytes. This decrease was independent of the changes in the gut microbiota and dysbiosis caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted in a Nod2 -deficient mixed bone marrow (BM) chimera. The use of pharmacological inhibitors revealed that activation of NOD2 during monocyte-derived cell development, dominantly inhibits mTOR-mediated macrophage differentiation in a TNFα-dependent manner. These observations were supported by the identification of a TNFα-dependent response to muramyl dipeptide (MDP) that is specifically lost when CD14-expressing blood cells bear a frameshift mutation in NOD2. Conclusion: NOD2 negatively regulates a macrophage developmental program through a feed-forward loop that could be exploited for overcoming resistance to anti-TNF therapy in CD. 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, Alvarez-Simon, Radulovic, Boulard, Laine, Delacre, Waldschmitt, Segura, Kluza, Chamaillard and Poulin.)
Databáze:	MEDLINE
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