M1 Macrophages Activate Notch Signalling in Epithelial Cells: Relevance in Crohn's Disease

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Crohn's disease (CD) treatment aims for mucosal regeneration, a process involving macrophages and the Notch signalling pathway.
• Macrophages exhibit diverse phenotypes (M1/M2) with varying expression of surface proteins, cytokines, and hypoxia-inducible factors (HIFs).

Purpose of the Study:

• To investigate the role of HIFs in Notch ligand expression by macrophages.
• To determine the relevance of this pathway in mucosal regeneration in Crohn's disease.

Main Methods:

• Human monocytes and U937-derived macrophages were polarized to M1 and M2 phenotypes.
• Expression of HIF-1α, HIF-2α, Jagged 1 (Jag1), and delta-like 4 (Dll4) was evaluated.
• Co-cultures assessed macrophage effects on epithelial hairy and enhancer of split-1 (HES1) and intestinal alkaline phosphatase (IAP) expression.
• Macrophage phenotypes and Notch signalling were analyzed in CD patient mucosa.

Main Results:

• M1 macrophages demonstrated HIF-1-dependent induction of Jag1 and Dll4, increasing HES1 and IAP in epithelial cells.
• In CD patients, M1 macrophages expressed HIF-1α and Jag1, while M2 macrophages expressed HIF-2α.
• A correlation was observed between the M1/M2 macrophage ratio and HES1/IAP protein levels.

Conclusions:

• M1 macrophages, not M2, induce Notch ligands via HIF-1, activating epithelial Notch signaling.
• In chronic CD, M2 macrophage prevalence correlates with reduced Notch signalling and impaired enterocyte differentiation.