Journal
SCIENCE ADVANCES
Volume 7, Issue 19, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe5171
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Funding
- National Natural Science Foundation of China [31970889, 31622023]
- Innovation Program of Shanghai Municipal Education Commission [201901070007E00022]
- Key fund for basic research of Shanghai Science and Technology Commission [20JC1417700]
- Shanghai Municipal Natural Science Foundation [19ZR1461800]
- Outstanding academic leader program of Shanghai health and Family Planning Commission [2017BR024]
- Shuguang Program of Shanghai Municipal Education Commission [17SG24]
- Fundamental Research Funds for the Central Universities
- Innovative research team of high-level local universities in Shanghai
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Deficiency of c-Cbl in DCs exacerbates DSS-induced colitis through suppressing fungal-induced activation of RelB. Treatment with DPH synergistically enhances fungi-induced c-Cbl activation to restrict colitis in mice.
Intestinal fungi are critical for modulating host immune homeostasis and underlying mechanisms remain unclear. We show that dendritic cell (DC)-specific deficiency of casitas B-lineage lymphoma (c-Cbl) renders mice susceptible to dextran sodium sulfate (DSS)-induced colitis. Mechanistically, we identify that c-Cbl functions downstream of Dectin-2 and Dectin-3 to mediate the ubiquitination and degradation of noncanonical nuclear factor kappa B subunit RelB. Thus, c-Cbl deficiency in DCs promotes alpha-mannan-induced activation of RelB, which suppresses p65-mediated transcription of an anti-inflammatory cytokine gene, il10, thereby aggravating DSS-induced colitis. Moreover, suppressing fungal growth with fluconazole or inhibition of RelB activation in vivo attenuates colitis in mice with DC-specific deletion of c-Cbl. We also demonstrate an interaction between c-Cbl and c-Abl tyrosine kinase and find that treatment with DPH, a c-Abl agonist, synergistically increases fungi-induced c-Cbl activation to restrict colitis. Together, these findings unravel a previously unidentified fungi-induced c-Cbl/RelB axis that sustains intestinal homeostasis and protects against intestinal inflammation.
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