Loss of NOD2 in macrophages improves colitis and tumorigenesis in a lysozyme-dependent manner

Front Immunol. 2023 Oct 9:14:1252979. doi: 10.3389/fimmu.2023.1252979. eCollection 2023.

Abstract

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 LysMCre/+;Nod2fl/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, LysMCre/+;Nod2fl/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 LysMCre/+;Nod2fl/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.

Keywords: NOD2; cancer-associated colitis; colitis; lysozyme; myeloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane
  • Colitis* / chemically induced
  • Colitis* / genetics
  • Colitis* / metabolism
  • Crohn Disease*
  • Macrophages* / metabolism
  • Mice
  • Muramidase / genetics
  • Nod2 Signaling Adaptor Protein* / genetics

Substances

  • Azoxymethane
  • Muramidase
  • Nod2 protein, mouse
  • Nod2 Signaling Adaptor Protein

Grants and funding

This work was funded by the French government’s ATIP-Avenir program and by the Fondation Recherche Médicale” (grant number EQU202103012718). LP also received a fellowship from the ATIP-Avenir program and funding support from the French National IBD Patients’ Association [Association François Aupetit (AFA)] and by the cancer charity “Comité du nord de la Ligue Nationale contre le Cancer”. CC received a fellowship funded by the cancer charity “La Ligue contre le cancer”. PRé was supported by La Ligue Contre le Cancer (TANC16319).