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

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 TGFβ1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGFβ1 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. Teaser Interleukin-11 stalls type 2-to-type 1 alveolar epithelial cell differentiation and prevents lung regeneration ### Competing Interest Statement S.A.C is a co-inventor of the patent applications (WO/2017/103108) and (WO/2018/109170). S.A.C., W.-W.L. and B.N are co-inventors of the patent application (WO/2019/073057). S.A.C. is a co-founder and shareholder of Enleofen Bio PTE LTD, a company that develops anti-IL11 therapeutics, which were acquired for further development by Boehringer Ingelheim. All other authors declare no competing interests.