Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China.
Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Sci Adv. 2021 May 7;7(19). doi: 10.1126/sciadv.abe5171. Print 2021 May.
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 κB subunit RelB. Thus, c-Cbl deficiency in DCs promotes α-mannan-induced activation of RelB, which suppresses p65-mediated transcription of an anti-inflammatory cytokine gene, , 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.
肠道真菌对于调节宿主免疫稳态至关重要，但潜在机制尚不清楚。我们发现树突状细胞（DC）特异性缺失 Casitas B 细胞淋巴瘤（c-Cbl）会使小鼠易患葡聚糖硫酸钠（DSS）诱导的结肠炎。从机制上讲，我们确定 c-Cbl 作为 Dectin-2 和 Dectin-3 的下游因子发挥作用，介导非典型核因子κB 亚基 RelB 的泛素化和降解。因此，DC 中的 c-Cbl 缺乏会促进α-甘露聚糖诱导的 RelB 激活，从而抑制 p65 介导的抗炎细胞因子基因的转录，从而加重 DSS 诱导的结肠炎。此外，用氟康唑抑制真菌生长或体内抑制 RelB 激活可减轻 DC 特异性缺失 c-Cbl 的小鼠的结肠炎。我们还证明了 c-Cbl 和 c-Abl 酪氨酸激酶之间的相互作用，并发现用 DPH（一种 c-Abl 激动剂）治疗可协同增加真菌诱导的 c-Cbl 激活，从而限制结肠炎。总之，这些发现揭示了一个以前未被识别的真菌诱导的 c-Cbl/RelB 轴，该轴维持肠道稳态并防止肠道炎症。
