Immunology Discovery and Regenerative Medicine, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Joint Carnegie Mellon University-University of Pittsburgh Ph.D. Program in Computational Biology, Pittsburgh, PA 15213, USA.
Cell Rep. 2024 Aug 27;43(8):114569. doi: 10.1016/j.celrep.2024.114569. Epub 2024 Jul 31.
Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease.
针对急性损伤的伤口愈合是由实质细胞、基质细胞和免疫细胞的协调和短暂激活介导的，最终恢复到体内平衡状态。与炎症和衰老相关的环境、遗传和表观遗传因素可导致微环境的持续激活和纤维化。在这里，我们确定了白细胞介素 4（IL-4）细胞因子信号在间质巨噬细胞和 II 型肺泡上皮细胞（ATII）中的相反作用。我们表明，巨噬细胞中的 IL4Ra 信号促进博莱霉素诱导的肺损伤后肺泡上皮的再生。使用类器官和小鼠模型，我们表明 IL-4 直接作用于 ATII 的一个亚群，诱导转录因子 SOX9 的表达，并将其重新编程为具有气道和肺泡谱系潜能的祖细胞样状态。在衰老和博莱霉素诱导的肺损伤的情况下，这导致上皮细胞分化和细支气管化生异常，与间质性肺病中观察到的细胞和组织学变化一致。
