Lautenberg Center for Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Nat Immunol. 2011 Mar;12(3):239-46. doi: 10.1038/ni.1994. Epub 2011 Jan 30.
Colonic homeostasis entails epithelium-lymphocyte cooperation, yet many participants in this process are unknown. We show here that epithelial microRNAs mediate the mucosa-immune system crosstalk necessary for mounting protective T helper type 2 (T(H)2) responses. Abolishing the induction of microRNA by gut-specific deletion of Dicer1 (Dicer1(Δgut)), which encodes an enzyme involved in microRNA biogenesis, deprived goblet cells of RELMβ, a key T(H)2 antiparasitic cytokine; this predisposed the host to parasite infection. Infection of Dicer1(Δgut) mice with helminths favored a futile T(H)1 response with hallmarks of inflammatory bowel disease. Interleukin 13 (IL-13) induced the microRNA miR-375, which regulates the expression of TSLP, a T(H)2-facilitating epithelial cytokine; this indicated a T(H)2-amplification loop. We found that miR-375 was required for RELMβ expression in vivo; miR-375-deficient mice had significantly less intestinal RELMβ, which possibly explains the greater susceptibility of Dicer1(Δgut) mice to parasites. Our findings indicate that epithelial microRNAs are key regulators of gut homeostasis and mucosal immunity.
肠道稳态需要上皮细胞-淋巴细胞的合作，但这个过程中的许多参与者尚不清楚。我们在这里表明，上皮细胞 microRNA 介导了粘膜免疫系统的串扰，这对于引发保护性辅助性 T 细胞 2（T(H)2）反应是必要的。通过肠道特异性敲除 Dicer1（Dicer1(Δgut)）来消除 microRNA 的诱导，Dicer1 编码一种参与 microRNA 生物发生的酶，剥夺了杯状细胞中的 RELMβ，这是一种关键的 T(H)2 抗寄生虫细胞因子；这使宿主易受寄生虫感染。用寄生虫感染 Dicer1(Δgut)小鼠有利于无效的 T(H)1 反应，具有炎症性肠病的特征。白细胞介素 13（IL-13）诱导 microRNA miR-375，它调节 T(H)2 促进上皮细胞因子 TSLP 的表达；这表明存在 T(H)2 扩增环。我们发现 miR-375 在体内对于 RELMβ 的表达是必需的；miR-375 缺陷小鼠的肠道 RELMβ 明显减少，这可能解释了 Dicer1(Δgut)小鼠对寄生虫更易感性的原因。我们的研究结果表明，上皮细胞 microRNA 是肠道稳态和粘膜免疫的关键调节剂。
