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bioRxiv · 10.1101/2022.11.11.516109

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Ng, B.·Huang, K. Y.·Pua, C. J.·Lim, W.-W.·Kuthubudeen, F.·Hii, A. A.·Viswanathan, S.·Petretto, E. G.·Cook, S. A.
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Abstract

Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGF{beta}1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGF{beta}1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion of Il11ra1 in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species. TeaserInterleukin-11 stalls type 2-to-type 1 alveolar epithelial cell differentiation and prevents lung regeneration

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Ng, B., Huang, K. Y., Pua, C. J., Lim, W.-W., Kuthubudeen, F., Hii, A. A., Viswanathan, S., Petretto, E. G., Cook, S. A.. 2022-11-12. Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration. https://doi.org/10.1101/2022.11.11.516109

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