IL-33 is a well-studied cytokine that resides normally within nuclei but can be released by cell damage or stress to then signal via a single receptor widely expressed on immune cells to promote host resistance and type 2 allergic immunity. In this issue of the JCI, Wu et al. used a well-established model of mouse Sendai viral infection to show that IL-33 was induced in distal lung airway epithelium, specifically in cell-cycling basal cells. IL-33 induced cell-cycling basal cells to expand and migrate into the alveolar compartment, presumably to restore barrier function. However, restoring barrier function with airway-derived cells may also result in persistent alveolar metaplasia. Surprisingly, nuclear IL-33 in this system acted cell autonomously, independently of release and conventional ST2 (IL1RL1) receptor signaling. The findings uncover a signaling role for nuclear IL-33 in viral activation of mouse basal cells and add to the well-known "alarmin" function of IL-33.

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The key role of extracellular matrices in alveolar epithelial cell (AEC) biology is highlighted by the phenotypes of primary AECs cultured on a soft laminin gel contrasted with that on a stiff, fibronectin matrix. On laminin, AECs maintain an epithelial phenotype, and progenitor cells within this population proliferate. In contrast, on fibronectin, AECs rapidly lose surfactant expression and spread extensively, changes that depend on activation of latent TGF-β1 by engagement of fibronectin-binding integrins. The progenitor subpopulation responding to TGF-β1 undergoes epithelial mesenchymal transition (EMT). Although it remains uncertain to what degree EMT contributes directly to collagen 1 production, signaling pathways critical to EMT are important for repair and fibrosis, implying that EMT is part of the general program of lung repair. EMT reprogramming requires not only Smad signaling but also pY654-β-catenin. Generation of pY654-β-catenin requires assembly of complexes of the integrin α3β1, E-cadherin, and TGF-β1 receptors, and such assembly is a function of cell-cell and cell-matrix contacts. Sequestration of α3β1 or E-cadherin in such contacts prevents complex assembly, TGF-β1 induced pY654-β-catenin generation and EMT. Disruption of these contacts is a signal for the cells to initiate repair. Critical remaining questions center around better definition of direct versus indirect effects of EMT on collagen deposition and the nature of AEC progenitors differentiating during fibrogenesis. Elucidation of specific inhibitors of EMT should further test the question of whether the process is important to fibrosis in vivo and a viable therapeutic target.