TY - JOUR T1 - Interleukin-11 disrupts alveolar epithelial progenitor function JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00679-2022 VL - 9 IS - 3 SP - 00679-2022 AU - Rosa K. Kortekaas AU - Kerstin E. Geillinger-Kästle AU - Theo Borghuis AU - Kaoutar Belharch AU - Megan Webster AU - Wim Timens AU - Janette K. Burgess AU - Reinoud Gosens Y1 - 2023/05/01 UR - http://openres.ersjournals.com/content/9/3/00679-2022.abstract N2 - Background Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. In IPF there is disrupted alveolar structural architecture, yet the effect of IL-11 on the dysregulated alveolar repair remains to be elucidated.Methods We hypothesised that epithelial-fibroblast communication associated with lung repair is disrupted by IL-11. Thus, we studied whether IL-11 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 IL-11 and IL-11 receptor (IL-11R) in human control and IPF lungs using immunohistochemistry.Results IL-11 protein was observed in airway epithelium, macrophages and in IPF lungs, also in areas of alveolar type 2 (AT2) cell hyperplasia. IL-11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid number and reduced the fraction of Prosurfactant Protein C-expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS exposed to IL-11, ciliated cell markers were increased. The response of primary human fibroblasts to IL-11 on gene expression level was minimal, though bulk RNA-sequencing revealed IL-11 modulated various processes which are associated with IPF, including unfolded protein response, glycolysis and Notch signalling.Conclusions IL-11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. Evidence for a contribution of dysregulated fibroblast–epithelial communication to this process is limited.Interleukin-11 negatively impacts lung epithelial regeneration by inhibiting progenitor cell activation and suppressing alveolar differentiation https://bit.ly/3ZRDpIR ER -