Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China.
Front Immunol. 2018 Feb 2;9:119. doi: 10.3389/fimmu.2018.00119. eCollection 2018.
The intestinal mucosal barrier is critical for host defense against pathogens infection. Here, we demonstrate that the mixed lineage kinase-like protein (MLKL), a necroptosis effector, promotes intestinal epithelial barrier function by enhancing inflammasome activation. MLKL mice were more susceptible to infection compared with wild-type counterparts, with higher mortality rates, increased body weight loss, exacerbated intestinal inflammation, more bacterial colonization, and severe epithelial barrier disruption. MLKL deficiency promoted early epithelial colonization of prior to developing apparent intestinal pathology. Active MLKL was predominantly expressed in crypt epithelial cells, and experiments using bone marrow chimeras found that the protective effects of MLKL were dependent on its expression in non-hematopoietic cells. Intestinal mucosa of MLKL mice had impaired caspase-1 and gasdermin D cleavages and decreased interleukin (IL)-18 release. Moreover, administration of exogenous recombinant IL-18 rescued the phenotype of increased bacterial colonization in MLKL mice. Thus, our results uncover the role of MLKL in enhancing inflammasome activation in intestinal epithelial cells to inhibit early bacterial colonization.
肠道黏膜屏障对于宿主防御病原体感染至关重要。在这里，我们证明了混合谱系激酶样蛋白（MLKL）作为坏死性凋亡效应物，通过增强炎症小体激活来促进肠道上皮屏障功能。与野生型相比，MLKL 敲除小鼠更容易感染，死亡率更高，体重减轻更严重，肠道炎症更严重，细菌定植更多，上皮屏障破坏更严重。MLKL 缺乏促进了 在出现明显肠道病理学之前早期上皮定植。活性 MLKL 主要表达在隐窝上皮细胞中，使用骨髓嵌合体实验发现，MLKL 的保护作用依赖于其在非造血细胞中的表达。MLKL 敲除小鼠的 caspase-1 和 gasdermin D 切割以及白细胞介素（IL）-18 释放受损。此外，外源性重组 IL-18 的给药挽救了 MLKL 小鼠中增加的细菌定植表型。因此，我们的结果揭示了 MLKL 在增强肠道上皮细胞中炎症小体激活以抑制早期细菌定植中的作用。
