Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA.
Immunohorizons. 2024 Jul 1;8(7):478-491. doi: 10.4049/immunohorizons.2400047.
IκB kinase (IKK)α controls noncanonical NF-κB signaling required for lymphoid organ development. We showed previously that lymph node formation is ablated in IkkαLyve-1 mice constitutively lacking IKKα in lymphatic endothelial cells (LECs). We now reveal that loss of IKKα in LECs leads to the formation of BALT in the lung. Tertiary lymphoid structures appear only in the lungs of IkkαLyve-1 mice and are not present in any other tissues, and these highly organized BALT structures form after birth and in the absence of inflammation. Additionally, we show that IkkαLyve-1 mice challenged with influenza A virus (IAV) exhibit markedly improved survival and reduced weight loss compared with littermate controls. Importantly, we determine that the improved morbidity and mortality of IkkαLyve-1 mice is independent of viral load and rate of clearance because both mice control and clear IAV infection similarly. Instead, we show that IFN-γ levels are decreased, and infiltration of CD8 T cells and monocytes into IkkαLyve-1 lungs is reduced. We conclude that ablating IKKα in LECs promotes BALT formation and reduces the susceptibility of IkkαLyve-1 mice to IAV infection through a decrease in proinflammatory stimuli.
IKK 激酶 (IKK)α 控制非经典 NF-κB 信号通路，该信号通路对于淋巴器官的发育是必需的。我们之前曾表明，在淋巴内皮细胞 (LEC) 中持续缺乏 IKKα 的 IkkαLyve-1 小鼠中，淋巴结的形成被消除。现在我们揭示了 LEC 中 IKKα 的缺失会导致肺中 BALT 的形成。三级淋巴结构仅出现在 IkkαLyve-1 小鼠的肺部，而不存在于任何其他组织中，这些高度组织化的 BALT 结构在出生后和没有炎症的情况下形成。此外，我们还表明，与同窝对照相比，流感 A 病毒 (IAV) 感染的 IkkαLyve-1 小鼠的存活率显著提高，体重减轻减少。重要的是，我们确定 IkkαLyve-1 小鼠的发病率和死亡率的改善与病毒载量和清除率无关，因为这两种小鼠对 IAV 感染的控制和清除情况相似。相反，我们表明 IFN-γ 水平降低，并且 CD8 T 细胞和单核细胞浸润到 IkkαLyve-1 肺部的程度降低。我们得出结论，通过减少促炎刺激，在 LEC 中消除 IKKα 会促进 BALT 的形成，并降低 IkkαLyve-1 小鼠对 IAV 感染的易感性。
