1. IL-4-induced SOX9 confers lineage plasticity to aged adult lung stem cells.
- Author
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Cai, Xiaoyu T., Jia, Minxue, Heigl, Tobias, Shamir, Eliah R., Wong, Aaron K., Hall, Ben M., Arlantico, Alexander, Hung, Jeffrey, Menon, Hari G., Darmanis, Spyros, Brightbill, Hans D., Garfield, David A., and Rock, Jason R.
- Abstract
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. [Display omitted] • IL4Ra signaling in Cx3cr1
+ macrophages promotes regeneration of the lung epithelium • IL-4-induced Sox9 reprograms ATIIs into a fetal-like state with airway potential • Aging primes ATIIs with hyperresponsiveness to IL-4 cytokines • Loss of IL4Ra in ATIIs reduces its airway lineage potential and bleomycin-induced fibrosis Cai et al. have shown that type 2 cytokines directly impact adult epithelial stem cells by inducing Sox9 and lineage plasticity during aging. This link between aging, inflammation, and regenerative outcomes offers a potential strategy for the treatment of maladaptive epithelial remodeling in age-related and chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]- Published
- 2024
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