Nuclear IL-33 as a growth and survival agent within basal cells
Harold A. Chapman
Harold A. Chapman
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Commentary

Nuclear IL-33 as a growth and survival agent within basal cells

Abstract

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.

Authors

Harold A. Chapman

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Figure 1

Dual actions of mouse IL-33 in virus-induced alveolar injury.

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Dual actions of mouse IL-33 in virus-induced alveolar injury. The schema...
The schematic highlights the parallel pathways by which IL-33 orchestrates epithelial responses to Sendai virus infection. Responding to cell stress or death created by viral infection, AT2 cells release IL-33 from its nuclear localization (red nuclei) to the extracellular space, where signaling through its ST2 receptors activates an allergic type 2 immune response. AT2 proliferation and expansion seen after viral infections is independent of IL-33 presence or ST2 (IL1RL1) signaling. In contrast, viral infection also induces nuclear IL-33 release in a subpopulation of cycling basal cells, where it is critical for expansion and migration from distal airways and helps restore barrier function in engraftments within denuded alveolar regions. As basal cells have never been shown to transdifferentiate into AT2 cells, reconstituting the early barrier may occur at the expense of longer-term dysplastic changes, thus perpetuating inflammation and impairing a complete return to normalcy. Similar responses in human diseases such as COVID-19 and ARDS could help explain the bronchiolization and metaplastic basal cells widely observed by pathologists during these major injuries.