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Article Dans Une Revue Frontiers in Immunology Année : 2023

NOD2 in monocytes negatively regulates macrophage development through TNFalpha

Camille Chauvin
  • Fonction : Auteur
Daniel Alvarez-Simon
  • Fonction : Auteur
Katarina Radulovic
  • Fonction : Auteur
Olivier Boulard
  • Fonction : Auteur
William Laine
  • Fonction : Auteur
Myriam Delacre
  • Fonction : Auteur
Nadine Waldschmitt
  • Fonction : Auteur
Elodie Segura
  • Fonction : Auteur
Jérome Kluza
  • Fonction : Auteur
Mathias Chamaillard
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04276980 , version 1 (09-11-2023)

Identifiants

Citer

Camille Chauvin, Daniel Alvarez-Simon, Katarina Radulovic, Olivier Boulard, William Laine, et al.. NOD2 in monocytes negatively regulates macrophage development through TNFalpha. Frontiers in Immunology, 2023, 14, ⟨10.3389/fimmu.2023.1181823⟩. ⟨hal-04276980⟩

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