Epithelial cells are charged with protection at barrier sites, but whether this normally beneficial response might sometimes become dysfunctional still needs definition. Here, we recognized a pattern of imbalance marked by basal epithelial cell growth and differentiation that replaced normal airspaces in a mouse model of progressive postviral lung disease due to the Sendai virus. Single-cell and lineage-tracing technologies identified a distinct subset of basal epithelial stem cells (basal ESCs) that extended into gas-exchange tissue to form long-term bronchiolar-alveolar remodeling regions. Moreover, this cell subset was selectively expanded by crossing a cell-growth and survival checkpoint linked to the nuclear-localized alarmin IL-33 that was independent of IL-33 receptor signaling and instead connected to autocrine chromatin accessibility. This mechanism creates an activated stem-progenitor cell lineage with potential for physiological or pathological function. Thus, conditional loss of Il33 gene function in basal epithelial cells disrupted the homeostasis of the epithelial barrier at skin and gut sites but also markedly attenuated postviral disease in the lung based on the downregulation of remodeling and inflammation. Thus, we define a basal ESC strategy to deploy innate immune machinery that appears to overshoot the primordial goal of self-defense. Our findings reveal new targets to stratify and correct chronic and often deadly postviral disease.

中文翻译：

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基底上皮干细胞越过病毒后肺病的警报检查点

上皮细胞在屏障部位具有保护作用，但这种通常有益的反应是否有时会变得功能失调仍然需要定义。在这里，我们发现了一种以基底上皮细胞生长和分化为标志的不平衡模式，这种模式取代了仙台病毒引起的进行性病毒后肺病小鼠模型中的正常空间。单细胞和谱系追踪技术确定了一个独特的基底上皮干细胞（基底 ESC）子集，它们延伸到气体交换组织中，形成长期的细支气管-肺泡重塑区域。此外，该细胞亚群通过跨越与核定位警报素 IL-33 相关的细胞生长和存活检查点进行选择性扩增，该警报素 IL-33 独立于 IL-33 受体信号传导，而是与自分泌染色质可及性相关。这种机制产生了具有生理或病理功能潜力的活化干祖细胞谱系。因此，有条件的损失基底上皮细胞中的Il33基因功能破坏了皮肤和肠道部位上皮屏障的稳态，但也基于重塑和炎症的下调显着减轻了肺中的病毒后疾病。因此，我们定义了一个基本的 ESC 策略来部署先天免疫机制，这似乎超出了自卫的原始目标。我们的研究结果揭示了分层和纠正慢性且通常是致命的病毒后疾病的新目标。