LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE

Simon D. Pouwels*, Laura Hesse, Xinhui Wu, Venkata Sita Rama Raju Allam, Daan van Oldeniel, Linsey J. Bhiekharie, Simon Phipps, Brian G. Oliver, Reinoud Gosens, Maria B. Sukkar, Irene H. Heijink

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)
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Abstract

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastaseinduced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.

Original languageEnglish
Pages (from-to)L641-L652
Number of pages12
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume321
Issue number4
DOIs
Publication statusPublished - Oct-2021

Keywords

  • COPD
  • emphysema
  • organoids
  • precision cut lung slices
  • RAGE
  • GLYCATION END-PRODUCTS
  • SMOKE-INDUCED EMPHYSEMA
  • INDUCED DAMP RELEASE
  • SUSCEPTIBILITY
  • RECEPTOR
  • INFLAMMATION
  • DISEASE

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