IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration
IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration
复制标题
白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNFα）有助于形成炎性微环境以促进肺泡再生
DOI：
10.1016/j.stemcr.2019.02.013
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发表时间：
2019-04-09
影响因子：
5.9
通讯作者：
Hogan, Brigid L. M.
中科院分区：
文献类型：
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作者：
Katsura, Hiroaki;Kobayashi, Yoshihiko;Hogan, Brigid L. M.
众所周知，炎症反应有助于损伤后的组织恢复。然而，促进肺泡再生的确切机制尚不清楚。在这里，使用基于类器官的筛选试验，我们发现白细胞介素-1 （IL-1）和肿瘤坏死因子α (TNF - α)在维持AEC2s分化能力的同时增强了AEC2s的增殖。此外，我们发现，在体内流感诱导的AEC2损伤后，IL-1 β和TNF α的表达在AEC2生态位中被诱导，谱系追踪分析显示，受损区域周围存活的AEC2s有助于肺泡再生。通过对IL-1核因子κ B （nf - κ B）信号轴多个组分的遗传和药理学调控，我们发现细胞内在和间质介导的IL-1信号对于AEC2介导的肺再生至关重要。综上所述，我们提出IL-1/TNF α - nf - κ B信号轴作为炎症相关生态位的一个组成部分，调节存活的AEC2s的增殖并促进肺再生。
Inflammatory responses are known to facilitate tissue recovery following injury. However, the precise mechanisms that enhance lung alveolar regeneration remain unclear. Here, using an organoid-based screening assay, we find that interleukin-1 (IL-1) and tumor necrosis factor alpha(TNF alpha) enhance the proliferation of AEC2s while maintaining their differentiation capacity. Furthermore, we find that expression of IL-1 beta and TNF alpha are induced in the AEC2 niche following influenza-induced injury in vivo, and lineage tracing analysis revealed that surviving AEC2s around the damaged area contribute to alveolar regeneration. Through genetic and pharmacological modulation of multiple components of the IL-1-nuclear factor kappa B (NF-kappa B) signaling axis, we show that cell-intrinsic as well as stromal mediated IL-1 signaling are essential for AEC2 mediated lung regeneration. Taken together, we propose that the IL-1/TNF alpha-NF-kappa B signaling axis functions as a component of an inflammation-associated niche to regulate proliferation of surviving AEC2s and promote lung regeneration.