Key Points The canonical Wnt pathway in intestinal APCs protects against CAC. LRP5/6–β-catenin–IL-10 signaling in APCs suppresses chronic intestinal inflammation. This pathway plays an important role in regulating intestinal commensal homeostasis. Loss of immune tolerance to gut microflora is inextricably linked to chronic intestinal inflammation and colitis-associated colorectal cancer (CAC). The LRP5/6 signaling cascade in APCs contributes to immune homeostasis in the gut, but whether this pathway in APCs protects against CAC is not known. In the current study, using a mouse model of CAC, we show that the LRP5/6–β-catenin–IL-10 signaling axis in intestinal CD11c+ APCs protects mice from CAC by regulating the expression of tumor-promoting inflammatory factors in response to commensal flora. Genetic deletion of LRP5/6 in CD11c+ APCs in mice (LRP5/6ΔCD11c) resulted in enhanced susceptibility to CAC. This is due to a microbiota-dependent increased expression of proinflammatory factors and decreased expression of the immunosuppressive cytokine IL-10. This condition could be improved in LRP5/6ΔCD11c mice by depleting the gut flora, indicating the importance of LRP5/6 in mediating immune tolerance to the gut flora. Moreover, mechanistic studies show that LRP5/6 suppresses the expression of tumor-promoting inflammatory factors in CD11c+ APCs via the β-catenin–IL-10 axis. Accordingly, conditional activation of β-catenin specifically in CD11c+ APCs or in vivo administration of IL-10 protected LRP5/6ΔCD11c mice from CAC by suppressing the expression of inflammatory factors. In summary, in this study, we identify a key role for the LRP5/6–β-catenin–IL-10 signaling pathway in intestinal APCs in resolving chronic intestinal inflammation and protecting against CAC in response to the commensal flora.

中文翻译：

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肠道 APC 中的 Wnt-β-Catenin-IL-10 信号轴保护小鼠免受结肠炎相关结肠癌的影响，以应对肠道微生物群

关键点 肠道 APC 中的经典 Wnt 通路可防止 CAC。APCs中的LRP5/6-β-catenin-IL-10信号抑制慢性肠道炎症。该途径在调节肠道共生稳态中起重要作用。对肠道微生物群的免疫耐受性丧失与慢性肠道炎症和结肠炎相关的结直肠癌 (CAC) 密不可分。APCs 中的 LRP5/6 信号级联有助于肠道中的免疫稳态，但 APCs 中的这一途径是否可以防止 CAC 尚不清楚。在目前的研究中，使用 CAC 的小鼠模型，我们表明肠道 CD11c+ APC 中的 LRP5/6-β-catenin-IL-10 信号轴通过调节促肿瘤炎症因子的表达来保护小鼠免受 CAC 的侵害。共生植物群。小鼠 CD11c+ APC 中 LRP5/6 的基因缺失 (LRP5/6ΔCD11c) 导致对 CAC 的易感性增强。这是由于微生物群依赖的促炎因子表达增加和免疫抑制细胞因子 IL-10 表达减少。通过消耗肠道菌群可以改善 LRP5/6ΔCD11c 小鼠的这种情况，表明 LRP5/6 在介导对肠道菌群的免疫耐受中的重要性。此外，机制研究表明，LRP5/6 通过 β-catenin-IL-10 轴抑制 CD11c+ APC 中促肿瘤炎症因子的表达。因此，在 CD11c+APC 中特异性激活 β-catenin 或在体内施用 IL-10 可通过抑制炎症因子的表达来保护 LRP5/6ΔCD11c 小鼠免受 CAC 影响。总之，在本研究中，