E3 ligase c-Cbl regulates intestinal inflammation through suppressing fungi-induced noncanonical NF-κB activation

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Intestinal fungi play a crucial role in host immune homeostasis.
• The precise mechanisms by which fungi modulate the gut immune system are not fully understood.
• Dendritic cells (DCs) are key immune cells involved in maintaining intestinal balance.

Purpose of the Study:

• To elucidate the role of casitas B-lineage lymphoma (c-Cbl) in dendritic cells in regulating intestinal immunity and fungal interactions.
• To identify the molecular pathways involving c-Cbl in response to intestinal fungi.
• To explore therapeutic strategies targeting the c-Cbl pathway for inflammatory bowel diseases.

Main Methods:

• Utilized mouse models with DC-specific deficiency of c-Cbl.
• Induced colitis using dextran sodium sulfate (DSS).
• Investigated molecular mechanisms involving Dectin-2, Dectin-3, c-Cbl, RelB, and IL-10.
• Administered fluconazole and a c-Abl agonist (DPH) to assess therapeutic effects.

Main Results:

• DC-specific c-Cbl deficiency exacerbated DSS-induced colitis.
• c-Cbl mediates ubiquitination and degradation of RelB downstream of Dectin-2/3.
• c-Cbl deficiency led to increased RelB activation, suppressing IL-10 production and worsening colitis.
• Antifungal treatment (fluconazole) or RelB inhibition attenuated colitis in c-cbl deficient mice.
• c-Cbl interacts with c-Abl tyrosine kinase; DPH treatment restricted colitis.

Conclusions:

• Identified a novel fungi-induced c-Cbl/RelB signaling axis in dendritic cells.
• This pathway is critical for maintaining intestinal homeostasis and preventing inflammation.
• Targeting the c-Cbl/RelB axis or fungal load presents a potential therapeutic strategy for colitis.