c-Jun N-末端激酶 2 促进发炎肠道中的肠细胞存活和杯状细胞分化。,Mucosal Immunology

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c-Jun N-末端激酶 2 促进发炎肠道中的肠细胞存活和杯状细胞分化。
Mucosal Immunology ( IF 7.9 ) Pub Date : 2017-09-01 , DOI: 10.1038/mi.2016.125
A D Mandić ₁ , E Bennek ₁ , J Verdier ₁ , K Zhang ₂ , S Roubrocks ₁ , R J Davis ₃ , B Denecke ₄ , N Gassler ₅ , K Streetz ₁ , A Kel ₆ , M Hornef ₂ , F J Cubero ₁ , C Trautwein ₁ , G Sellge ₁

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c-Jun N 末端激酶 (JNK) 有助于免疫信号传导，但它们在肠粘膜炎症期间的功能作用仍未明确。使用遗传小鼠模型，我们描述了 JNK1 和 JNK2 在稳态和急性结肠炎期间的作用。在肠上皮特异性 (ΔIEC) 或完全 JNK1 和骨髓嵌合或完全 JNK2 缺陷小鼠以及双基因敲除动物 (JNK1 ^ΔIEC JNK2 ^-/-) 在稳态和急性葡聚糖硫酸钠 (DSS) 诱导的结肠炎期间。使用人类 HT-29 细胞和野生型或 JNK2 缺陷型小鼠肠道类器官培养物证实了结果。我们表明，非造血 JNK2 而不是 JNK1 表达可保护免受 DSS 诱导的肠道炎症，减少上皮屏障功能障碍和肠细胞凋亡。JNK2 还增强了 Atonal 同系物 1 的表达、杯状细胞和肠内分泌细胞分化以及炎症条件下的粘液产生。我们的结果确定了上皮 JNK2 信号传导在炎症组织损伤时维持粘膜屏障功能、上皮细胞完整性和粘液层产生的保护作用。

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c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine.

c-Jun N-terminal kinases (JNKs) contribute to immune signaling but their functional role during intestinal mucosal inflammation has remained ill defined. Using genetic mouse models, we characterized the role of JNK1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation, and barrier function were analyzed in intestinal epithelium-specific (ΔIEC) or complete JNK1 and bone marrow chimeric or complete JNK2 deficient mice as well as double-knockout animals (JNK1^ΔIECJNK2^-/-) during homeostasis and acute dextran sulfate sodium (DSS)-induced colitis. Results were confirmed using human HT-29 cells and wild-type or JNK2-deficient mouse intestinal organoid cultures. We show that nonhematopoietic JNK2 but not JNK1 expression confers protection from DSS-induced intestinal inflammation reducing epithelial barrier dysfunction and enterocyte apoptosis. JNK2 additionally enhanced Atonal homolog 1 expression, goblet cell and enteroendocrine cell differentiation, and mucus production under inflammatory conditions. Our results identify a protective role of epithelial JNK2 signaling to maintain mucosal barrier function, epithelial cell integrity, and mucus layer production in the event of inflammatory tissue damage.

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