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IL-11 disrupts alveolar epithelial progenitor function
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IL-11 disrupts alveolar epithelial progenitor function
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IL-11 disrupts alveolar epithelial progenitor function
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Paper
IL-11 disrupts alveolar epithelial progenitor function
2022
Overview
IL11 is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. The alveolar architecture is disrupted in IPF, yet the effect of IL11 on dysregulated alveolar repair associated with IPF remains to be elucidated. We hypothesized that epithelial-fibroblast communication associated with lung repair is disrupted by IL11. Thus, we studied whether IL11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL11 and IL11 receptor in human control and IPF lungs using immunohistochemistry. IL11 protein was observed in human control lungs in airway epithelium, macrophages and in IPF lungs, in areas of AT2 cell hyperplasia. IL11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid cocultures of epithelial cells with lung fibroblasts, IL11 decreased organoid number and reduced the fraction of pro-SPC expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS alveolar marker gene expression declined, whereas airway markers were increased. The response of primary human fibroblasts to IL11 on gene expression level was minimal, though bulk RNAsequencing revealed IL11 modulated a number of processes which may play a role in IPF, including unfolded protein response, glycolysis and Notch signaling. In conclusion, IL11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. The contribution of dysregulated fibroblast epithelial communication to this process appears to be limited.Competing Interest StatementThis research was supported by an unrestricted research grant from Boehringer Ingelheim to the University of Groningen. Kerstin E. Geillinger-Kaestle and Megan Webster were employed by Boehringer Ingelheim when contributing to this manuscript.Footnotes* Supplemental files updated
