Monocyte intrinsic NOD2 signalling inhibits pathogenic macrophage differentiation and its loss in inflammatory macrophages improves intestinal inflammation - Archive ouverte HAL Access content directly
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Monocyte intrinsic NOD2 signalling inhibits pathogenic macrophage differentiation and its loss in inflammatory macrophages improves intestinal inflammation

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Abstract

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.

Dates and versions

hal-03870339 , version 1 (24-11-2022)

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Camille Chauvin, Daniel Alvarez Simon, Katarina Radulovic, Olivier Boulard, William Laine, et al.. Monocyte intrinsic NOD2 signalling inhibits pathogenic macrophage differentiation and its loss in inflammatory macrophages improves intestinal inflammation. 2022. ⟨hal-03870339⟩
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