Title :

Monocyte intrinsic NOD2 signalling inhibits pathogenic macrophage differentiation and its loss in inflammatory macrophages improves intestinal inflammation

Author(s) :

Chauvin, Camille [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Simon, Daniel Alvarez [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Radulovic, Katarina [Auteur]
Centre hospitalier [Valenciennes, Nord]
Boulard, Olivier [Auteur]
Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 [PHYCELL]
Laine, William [Auteur]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Delacre, Myriam [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Waldschmitt, Nadine [Auteur]
Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] [TUM]
Segura, Elodie [Auteur]
Immunité et cancer [U932]
Kluza, Jérome [Auteur]
Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Chamaillard, Mathias [Auteur]
Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 [PHYCELL]
POULIN, Lionel [Auteur]
Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 [PHYCELL]

HAL domain(s) :

Sciences du Vivant [q-bio]/Immunologie

English abstract : [en]

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 ...
Show more >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). We next asked whether Nod2 in either monocytes or tissue macrophages have distinct resolving properties in colitis.Results Despite a similar abundance of monocytes, the intestinal frequency of mo-DCs from Nod2-deficient mice was lowered independently of the changes in the gut microbiota that are caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted with mobilized bone marrow Nod2-deficient cells. The use of pharmacological inhibitors revealed that activated NOD2 at an early stage of development dominantly inhibits mTOR-mediated macrophage differentiation in a TNFalpha-dependent manner. These observations were supported by the identification of a TNFalpha-dependent response to MDP that is specifically lost in CD14-expressing blood cells bearing the frameshift mutation in NOD2. Accordingly, loss of NOD2 in monocytes lowers glycolytic reserve, CD115 expression and pro-resolving features. Dietary intake of aryl hydrocarbon receptor (AHR) agonists that promotes mo-DCs generation improves colitis in Nod2-deficient mice to the same extent as what is observed upon macrophage ablation of 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.Show less >

Language :

Anglais

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL