Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity.
Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity.
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上皮内膜IKKα表达调节3组先天淋巴样细胞反应和抗菌免疫。
DOI：
10.1084/jem.20141831
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发表时间：
2015-09-21
期刊：
影响因子：
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通讯作者：
Artis D
中科院分区：
文献类型：
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作者：
Giacomin PR;Moy RH;Noti M;Osborne LC;Siracusa MC;Alenghat T;Liu B;McCorkell KA;Troy AE;Rak GD;Hu Y;May MJ;Ma HL;Fouser LA;Sonnenberg GF;Artis D
IKKα在肠上皮细胞中的表达促进第3组先天淋巴样细胞产生IL-22，该轴对于防御啮齿类柠檬酸杆菌感染和限制DSS治疗后的肠道炎症至关重要。先天性淋巴样细胞（ILC）是维持粘膜表面上皮屏障完整性的关键，然而，调节ILC反应的组织特异性因子仍然缺乏特征。使用肠上皮细胞（IEC）特异性缺失κB激酶（IKK）α或IKKβ（NFκB激活的两个关键调节因子）抑制剂的小鼠，我们证明IEC内在IKKα表达选择性调节肠道中第3组ILC（ILC 3）依赖性抗菌免疫。尽管IKKβΔIEC小鼠有效控制了啮齿类柠檬酸杆菌感染，但IKKαΔIEC小鼠表现出严重的肠道炎症，增加了细菌向外周器官的传播，并增加了宿主死亡率。与对C的先天免疫力减弱一致。IKKαΔIEC小鼠的RORγt+ ILC 3s产生IL-22的能力受损，给予rIL-22或转移对照小鼠的分选纯化的IL-22活性ILCs可保护IKKαΔIEC小鼠免受C.啮齿动物引起的发病率IKKαΔIEC小鼠中ILC 3反应缺陷与IEC过度产生胸腺基质淋巴细胞生成素（TSLP）有关，TSLP负性调节ILC 3产生IL-22并损害对C.啮齿动物。在化学诱导的肠损伤和结肠炎后，IEC-内在IKKα表达对肠道炎症的调节同样至关重要。总的来说，这些数据确定了上皮细胞内在IKKα表达和TSLP在调节维持肠屏障免疫所需的ILC 3应答中的先前未被认识的作用。
Expression of IKKα in intestinal epithelial cells promotes IL-22 production by group 3 innate lymphoid cells, and this axis is essential for defense against Citrobacter rodentium infection and to limit intestinal inflammation in response to DSS treatment. Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)–specific deletions in either inhibitor of κB kinase (IKK)α or IKKβ, two critical regulators of NFκB activation, we demonstrate that IEC-intrinsic IKKα expression selectively regulates group 3 ILC (ILC3)–dependent antibacterial immunity in the intestine. Although IKKβΔIEC mice efficiently controlled Citrobacter rodentium infection, IKKαΔIEC mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKKαΔIEC mice displayed impaired IL-22 production by RORγt+ ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22–competent ILCs from control mice could protect IKKαΔIEC mice from C. rodentium–induced morbidity. Defective ILC3 responses in IKKαΔIEC mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKKα expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell–intrinsic IKKα expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.