Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation
Open Access
- 4 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 5 (11)
- https://doi.org/10.1172/jci.insight.137189
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, 2SHC 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-beta. CH25H/2SHC/LXR is, thus, an inducible metabolic axis that programs AMs for efferocytic resolution of inflammation.Funding Information
- National Institute of Environmental Health Sciences (Z01 ES102005)
- National Heart, Lung, and Blood Institute (P50 HL073996)
- National Heart, Lung, and Blood Institute (K23 HL144916)
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