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25-Hydroxycholesterol exacerbates vascular leak during acute lung injury

Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution...

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Autores principales: Madenspacher, Jennifer H., Morrell, Eric D., McDonald, Jeffrey G., Thompson, Bonne M., Li, Yue, Birukov, Konstantin G., Birukova, Anna A., Stapleton, Renee D., Alejo, Aidin, Karmaus, Peer W., Meacham, Julie M., Rai, Prashant, Mikacenic, Carmen, Wurfel, Mark M., Fessler, Michael B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132150/
https://www.ncbi.nlm.nih.gov/pubmed/36821369
http://dx.doi.org/10.1172/jci.insight.155448
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author Madenspacher, Jennifer H.
Morrell, Eric D.
McDonald, Jeffrey G.
Thompson, Bonne M.
Li, Yue
Birukov, Konstantin G.
Birukova, Anna A.
Stapleton, Renee D.
Alejo, Aidin
Karmaus, Peer W.
Meacham, Julie M.
Rai, Prashant
Mikacenic, Carmen
Wurfel, Mark M.
Fessler, Michael B.
author_facet Madenspacher, Jennifer H.
Morrell, Eric D.
McDonald, Jeffrey G.
Thompson, Bonne M.
Li, Yue
Birukov, Konstantin G.
Birukova, Anna A.
Stapleton, Renee D.
Alejo, Aidin
Karmaus, Peer W.
Meacham, Julie M.
Rai, Prashant
Mikacenic, Carmen
Wurfel, Mark M.
Fessler, Michael B.
author_sort Madenspacher, Jennifer H.
collection PubMed
description Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor–dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets. Here, using Ch25h(–/–) mice and exogenous 25HC in lung injury models, we provide evidence that 25HC sustains proinflammatory cytokines in the airspace and augments lung injury, at least in part, by inducing LXR-independent endoplasmic reticulum stress and endothelial leak. Suggesting an autocrine effect in endothelium, inhaled LPS upregulates pulmonary endothelial Ch25h, and non-hematopoietic Ch25h deletion is sufficient to confer lung protection. In patients with acute respiratory distress syndrome, airspace 25HC and alveolar macrophage CH25H were associated with markers of microvascular leak, endothelial activation, endoplasmic reticulum stress, inflammation, and clinical severity. Taken together, our findings suggest that 25HC deriving from and acting on different cell types in the lung communicates distinct, temporal LXR-independent and -dependent signals to regulate inflammatory homeostasis.
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spelling pubmed-101321502023-04-27 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury Madenspacher, Jennifer H. Morrell, Eric D. McDonald, Jeffrey G. Thompson, Bonne M. Li, Yue Birukov, Konstantin G. Birukova, Anna A. Stapleton, Renee D. Alejo, Aidin Karmaus, Peer W. Meacham, Julie M. Rai, Prashant Mikacenic, Carmen Wurfel, Mark M. Fessler, Michael B. JCI Insight Research Article Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor–dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets. Here, using Ch25h(–/–) mice and exogenous 25HC in lung injury models, we provide evidence that 25HC sustains proinflammatory cytokines in the airspace and augments lung injury, at least in part, by inducing LXR-independent endoplasmic reticulum stress and endothelial leak. Suggesting an autocrine effect in endothelium, inhaled LPS upregulates pulmonary endothelial Ch25h, and non-hematopoietic Ch25h deletion is sufficient to confer lung protection. In patients with acute respiratory distress syndrome, airspace 25HC and alveolar macrophage CH25H were associated with markers of microvascular leak, endothelial activation, endoplasmic reticulum stress, inflammation, and clinical severity. Taken together, our findings suggest that 25HC deriving from and acting on different cell types in the lung communicates distinct, temporal LXR-independent and -dependent signals to regulate inflammatory homeostasis. American Society for Clinical Investigation 2023-04-10 /pmc/articles/PMC10132150/ /pubmed/36821369 http://dx.doi.org/10.1172/jci.insight.155448 Text en © 2023 Madenspacher et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Madenspacher, Jennifer H.
Morrell, Eric D.
McDonald, Jeffrey G.
Thompson, Bonne M.
Li, Yue
Birukov, Konstantin G.
Birukova, Anna A.
Stapleton, Renee D.
Alejo, Aidin
Karmaus, Peer W.
Meacham, Julie M.
Rai, Prashant
Mikacenic, Carmen
Wurfel, Mark M.
Fessler, Michael B.
25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title_full 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title_fullStr 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title_full_unstemmed 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title_short 25-Hydroxycholesterol exacerbates vascular leak during acute lung injury
title_sort 25-hydroxycholesterol exacerbates vascular leak during acute lung injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132150/
https://www.ncbi.nlm.nih.gov/pubmed/36821369
http://dx.doi.org/10.1172/jci.insight.155448
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