School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin, United States.
Institute for Clinical and Translational Research, Madison, Wisconsin, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Jul 1;327(1):L86-L101. doi: 10.1152/ajplung.00066.2024. Epub 2024 May 7.
The mechanisms how aeroallergens induce sensitization are incompletely understood. The house dust mite (HDM) (Der p) is a ubiquitous aeroallergen that represents a major cause of allergic rhinitis and asthma. Herein, we tested whether HDM-induced aeroallergen exposure sensitivity is caused by the innate-immune response in small airway epithelial cells. HDM exposure is a rapid activator of NF-κB/RelA in the Secretoglobin (Scgb1a1+) lineage associated with upregulation of NF-κB/RelA-dependent markers of epithelial plasticity. To determine the effect of epithelial NF-κB signaling, NF-κB was depleted in a tamoxifen (TMX)-inducible -CreER mouse within a CL57B/L6 background. Corn oil or TMX-treated/RelA-depleted [RelA knockdown (KD)] mice were repetitively exposed to airway HDM challenges to induce airway hyperresponsiveness (AHR). Strikingly, we observed that HDM induces hallmarks of epithelial plasticity through upregulation of the mesenchymal core factors SNAI1 and ZEB1 and production of metalloproteinase (MMP)9 that are RelA-dependent. Downstream, HDM-induced mucous metaplasia, Th2 polarization, allergen sensitivity, and airway hyperreactivity were all reduced in the RelA-depleted mice. Mechanistically, HDM-induced functional and structural barrier disruption was dependent on RelA signaling and associated with active MMP secretion into the bronchoalveolar lavage fluid. To establish the role of MMP2/9 in barrier disruption, we observe that a small-molecule MMP inhibitor (SB-3CT) blocked HDM-induced barrier disruption and activation of plasticity in naïve wild-type (WT) mice. Loss of functional barrier was associated with MMP disruption of zona occludens (ZO)-1 containing adherens junctions. Overall, this data indicates that host innate signaling in the Scgb1a1+ progenitors is directly linked to epithelial plasticity, MMP9 secretion, and enhanced barrier permeability that allows allergen penetration, sensitization producing allergic asthma (AA) in vivo. We propose that maintenance of epithelial integrity may reduce allergic sensitization and AA. Allergic asthma from house dust mite (HDM) allergy causes substantial morbidity. This study examines the dynamic changes in small airway epithelial cells in a mouse model of HDM exposure. Our findings indicate that NF-κB/RelA signaling mediates matrix metalloproteinase production, disrupting the epithelial barrier resulting in allergic sensitization. Our findings bring new insight into mechanisms for epithelial cell-state change in the allergen response, creating a potential therapeutic pathway for maintaining barrier function in asthma.
变应原如何诱导致敏的机制尚不完全清楚。屋尘螨（HDM）（Der p）是一种无处不在的变应原，是过敏性鼻炎和哮喘的主要病因。在此，我们测试了 HDM 诱导的变应原暴露敏感性是否是由小气道上皮细胞中的固有免疫反应引起的。HDM 暴露是 NF-κB/RelA 在与上皮可塑性的 NF-κB/RelA 依赖性标志物上调相关的 Secretoglobin（Scgb1a1+）谱系中的快速激活剂。为了确定上皮细胞 NF-κB 信号传导的影响，我们在 CL57B/L6 背景下，在 tamoxifen（TMX）诱导的 -CreER 小鼠中耗尽 NF-κB。玉米油或 TMX 处理/RelA 耗尽[RelA 敲低（KD）]的小鼠反复暴露于气道 HDM 挑战中，以诱导气道高反应性（AHR）。引人注目的是，我们观察到 HDM 通过上调间充质核心因子 SNAI1 和 ZEB1 以及产生金属蛋白酶（MMP）9 来诱导上皮细胞可塑性，而 MMP9 是 RelA 依赖性的。下游，RelA 耗尽的小鼠中，HDM 诱导的粘液化生、Th2 极化、变应原敏感性和气道高反应性均降低。从机制上讲，HDM 诱导的功能和结构屏障破坏依赖于 RelA 信号传导，并与 MMP 分泌到支气管肺泡灌洗液中有关。为了确定 MMP2/9 在屏障破坏中的作用，我们观察到一种小分子 MMP 抑制剂（SB-3CT）阻断了 HDM 诱导的 Naive WT 小鼠的屏障破坏和可塑性激活。功能性屏障的丧失与 MMP 破坏含有黏附连接的紧密连接蛋白（ZO）-1 有关。总的来说，这些数据表明，Scgb1a1+祖细胞中的宿主固有信号直接与上皮细胞可塑性、MMP9 分泌和增强的屏障通透性相关，这种通透性允许变应原穿透，致敏产生体内过敏性哮喘（AA）。我们提出，维持上皮完整性可能会减少过敏致敏和 AA。由屋尘螨（HDM）过敏引起的过敏性哮喘会导致大量发病率。本研究在 HDM 暴露的小鼠模型中检查了小气道上皮细胞的动态变化。我们的研究结果表明，NF-κB/RelA 信号转导介导基质金属蛋白酶的产生，破坏上皮屏障，导致过敏致敏。我们的发现为变应原反应中上皮细胞状态变化的机制提供了新的见解，为维持哮喘中的屏障功能开辟了潜在的治疗途径。
