Blocking DCIR mitigates colitis and prevents colorectal tumors by enhancing the GM-CSF-STAT5 pathway

Area of Science:

• Immunology
• Gastroenterology
• Oncology

Background:

• Dendritic cell immunoreceptor (DCIR; Clec4a2) is a C-type lectin receptor crucial for immune and bone homeostasis.
• The specific role of DCIR in the intestine remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of DCIR in intestinal inflammation and colorectal tumorigenesis.
• To explore DCIR as a potential therapeutic target for inflammatory bowel disease and colon cancer.

Main Methods:

• Utilized Clec4a2 knockout (KO) mice in dextran sodium sulfate (DSS)-induced colitis and azoxymethane-DSS-induced colorectal tumor models.
• Analyzed colonic tissue for immune cell infiltration, gene expression (STAT5, Csf2, Il17a, Cxcl2, tight junction genes), and effects of GM-CSF and anti-NA2 (DCIR ligand) administration.

Main Results:

• Clec4a2 KO mice exhibited reduced severity of DSS colitis and fewer intestinal tumors.
• DCIR deficiency led to enhanced STAT5 phosphorylation, increased Csf2 and tight junction gene expression, and suppressed Il17a and Cxcl2 in the colon.
• Reduced infiltration of neutrophils and myeloid-derived suppressor cells was observed in Clec4a2 KO mice.
• GM-CSF administration ameliorated colitis, while anti-GM-CSF exacerbated it.
• Blocking DCIR with anti-NA2 antibody ameliorated colitis and prevented tumor formation.

Conclusions:

• DCIR signaling blockade ameliorates experimental colitis and suppresses colonic tumor development.
• DCIR represents a promising therapeutic target for treating inflammatory bowel diseases and colorectal cancer.