Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation

Jennifer H. Madenspacher, Eric D. Morrell, Kymberly M. Gowdy, Jeffrey G. McDonald, Bonne M. Thompson, Ginger Muse, Jennifer Martinez, Seddon Thomas, Carmen Mikacenic, Jerry A. Nick, Edward Abraham, Stavros Garantziotis, Renee D. Stapleton, Julie M. Meacham, Mary Jane Thomassen, William J. Janssen, Donald N. Cook, Mark M. Wurfel, Michael B. Fessler

Research output: Contribution to journalArticle

Abstract

Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol 25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds the expression of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the antiinflammatory nuclear receptor, liver X receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung. Here, we show that, of natural oxysterols or sterols, 25HC is induced in the inflamed lung of mice and humans. Ch25h-/- mice fail to induce 25HC and LXR target genes in the lung after LPS inhalation and exhibit delayed resolution of airway neutrophilia, which can be rescued by systemic treatment with either 25HC or synthetic LXR agonists. LXR-null mice also display delayed resolution, suggesting that native oxysterols promote resolution. During resolution, Ch25h is induced in macrophages upon their encounter with apoptotic cells and is required for LXR-dependent prevention of AM lipid overload, induction of Mertk, efferocytic resolution of airway neutrophilia, and induction of TGF-β. CH25H/25HC/LXR is, thus, an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.

Original languageEnglish (US)
JournalJCI Insight
Volume5
Issue number11
DOIs
StatePublished - Jun 4 2020

Keywords

  • Cholesterol
  • Inflammation
  • Innate immunity
  • Macrophages
  • Pulmonology

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation'. Together they form a unique fingerprint.

  • Cite this

    Madenspacher, J. H., Morrell, E. D., Gowdy, K. M., McDonald, J. G., Thompson, B. M., Muse, G., Martinez, J., Thomas, S., Mikacenic, C., Nick, J. A., Abraham, E., Garantziotis, S., Stapleton, R. D., Meacham, J. M., Thomassen, M. J., Janssen, W. J., Cook, D. N., Wurfel, M. M., & Fessler, M. B. (2020). Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation. JCI Insight, 5(11). https://doi.org/10.1172/jci.insight.137189