Fbxw7 increases CCL2/7 in CX3CR1hi macrophages to promote intestinal inflammation

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Mononuclear phagocytes (MPh) in the intestine exhibit plasticity and are key players in Inflammatory Bowel Diseases (IBD) pathogenesis.
• The precise mechanisms underlying MPh involvement in IBD remain incompletely understood.

Purpose of the Study:

• To investigate the role of E3 ligase FBXW7 in the context of intestinal inflammation and IBD.
• To explore FBXW7's mechanism of action in regulating mononuclear phagocyte activity during colitis.

Main Methods:

• Correlation analysis of FBXW7 expression with IBD severity in human patients and mouse models.
• Utilizing myeloid-specific Fbxw7 knockout mice and adeno-associated virus-mediated short hairpin RNA (AAV-shFbxw7) for gene silencing.
• Assessing chemokine production (CCL2, CCL7) by colonic macrophages and MPh accumulation in colitis models.

Main Results:

• Increased FBXW7 expression in inflamed intestines correlated with IBD severity.
• Myeloid Fbxw7 deficiency conferred protection against DSS and TNBS-induced colitis.
• Fbxw7 deficiency reduced CCL2 and CCL7 production by colonic macrophages, decreasing pro-inflammatory MPh accumulation.
• AAV-shFbxw7 administration alleviated colitis and improved survival rates.

Conclusions:

• FBXW7 degrades EZH2 in macrophages, thereby promoting CCL2 and CCL7 expression.
• This mechanism enhances the recruitment of pro-inflammatory MPh to the colon during colitis.
• Targeting FBXW7 presents a potential therapeutic strategy for intestinal inflammation.