25-Hydroxycholesterol exacerbates vascular leak during acute lung injury

Abstract

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 (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 nonhematopoietic Ch25h deletion is sufficient to confer lung protection. In acute respiratory distress syndrome patients, 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 upon different cell types in the lung communicates distinct, temporal LXRindependent and -dependent signals to regulate inflammatory homeostasis.

25-Hydroxycholesterol in health and diseases

“…Enzyme responsible for 25-HC biogenesis is mainly the 25-hydroxylase (CH25H), which uses cholesterol and molecular oxygen as substrates and NADPH as a cofactor. This enzyme is expressed at low levels in several cell types, including hematopoietic cells, epithelial, and endothelial cells (ECs), but also in macrophages and lymphoid organs ( 53 , 54 , 55 ) ( Fig. 3 ).…”

“…Besides the role of 25-HC and 7α,25-DHC in immune response, several studies have reported a key role of these oxysterols in lung in response to respiratory infection. In mouse, high expression of Ch25h is observed in resident alveolar macrophages ( 54 ). When respiratory infection is mimicked by injection of LPS, Ch25h expression is induced particularly in pulmonary ECs and alveolar macrophages ( 54 , 104 ) and 25-HC levels are increased in lungs and bronchioalveolar lavage fluids ( 105 ).…”

“…In mouse, high expression of Ch25h is observed in resident alveolar macrophages ( 54 ). When respiratory infection is mimicked by injection of LPS, Ch25h expression is induced particularly in pulmonary ECs and alveolar macrophages ( 54 , 104 ) and 25-HC levels are increased in lungs and bronchioalveolar lavage fluids ( 105 ). High-dose LPS increases 25-HC levels and provokes a loss of the lung endothelial barrier integrity by disorganizing VE-cadherin assembly ( 54 ).…”

Cholesterol‐autoxidation metabolites in host defense against infectious diseases

“…For example, 25-OHC is overproduced in both human and mouse alveolar MUs as an agonist for the anti-inflammatory nuclear receptor LXR and may play a central role in the pathogenesis and resolution of pulmonary inflammation [62]. However, in lung injury mouse models, 25-OHC sustains the production of proinflammatory cytokines and increases lung injury to a certain extent by inducing LXR-independent ER stress and endothelial leak [63]. On the other hand, LXR activation protects mouse smooth muscle cells from 7-KC-induced cytotoxicity and apoptosis by ABCG1mediated lipid redistribution which hinders the incorporation of 7-KC into the lipid raft microdomains on the plasma membrane [45,64,65].…”

“…A recent study has revealed that 5,6-EC can activate the cysteinyl aspartate specific proteinase-3/7 (caspase-3/7)mediated apoptotic pathway by inducing mitochondrial membrane potential changes to produce ROS, which ultimately leads to apoptosis in human osteoma cells [116]. It is worthwhile to Produced by MU activation of TLR in response to pathogen invasion and has extensive antiviral activity [28,29] Regulates plasma cell/IgA production [7,41] Regulates the activation of inflammatory bodies by affecting the level of SREBP-2 [35][36][37][38][39] Acts as a ligand to activate nuclear receptors to regulate inflammatory damage after infection [62,63] Mediates the remodeling of cholesterol in the plasma membrane and limits the intracellular transmission of LM and Shigella fowleri Prevents cell damage caused by CDCs [92,98] 7-hydroxycholesterol (7-OHC)…”