NIH VideoCast - Novel Roles for Oxysterols in Resolution of Inflammation and Critical Illness

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Novel Roles for Oxysterols in Resolution of Inflammation and Critical Illness

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Air date:	Wednesday, January 27, 2016, 4:15:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 243 (39 Live, 204 On-demand)
Category:	Immunology
Runtime:	00:56:23
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	Immunology Interest Group Michael Fessler is a physician scientist who is a Senior Investigator and Deputy Chief of the Immunity, Inflammation, and Disease Laboratory of the intramural research program at NIEHS/NIH. Mike received his M.D. at Harvard Medical School in 1996, after which he completed an internal medicine residency at Massachusetts General Hospital from 1996-1999, and then a pulmonary-critical care fellowship at University of Colorado from 1999-2002. In 2006, after four years on faculty at National Jewish Hospital, Mike started as a Tenure Track Investigator at NIEHS, and, in 2013, he received tenure. His laboratory focuses on the innate immune response, with a particular interest in mechanisms by which cholesterol trafficking through macrophages and the lung regulates host defense. His laboratory has helped to define the role of cholesterol transporters in regulation of lung inflammation and immunity, the role of lipid rafts in TLR signaling, and the therapeutic potential of statins and Liver X Receptor agonists in preclinical models of lung disease. In 2012, Mike received the Carol Basbaum Award from the American Thoracic Society, and in 2015 was inducted into the American Society for Clinical Investigation. Talk Abstract: Recent reports have revealed there to be substantial steady state flux of cholesterol through the lung, and have interestingly indicated that cholesterol trafficking may be uniquely coupled to immune and inflammatory responses in this organ. The oxysterol-activated nuclear receptor, Liver X Receptor (LXR), is in particular positioned at the crossroads of lipid homeostasis and immunity as it coordinately promotes cellular cholesterol mobilization and suppresses NF-κB-dependent inflammation. Here, we identify cholesterol-25-hydroxylase (Ch25h)-derived 25-hydroxycholesterol (25HC) as a lipopolysaccharide (LPS)-induced oxysterol that is uniquely required for promoting LXR-dependent resolution of inflammation in the lung. LPS inhalation upregulates Ch25h in pulmonary macrophages, inducing 25HC in the murine and human airspace in vivo. Ch25h-null mice do not induce 25HC after LPS and display abrogated activation of LXR in the lungs and accumulation of lipid-laden macrophage ‘foam cells.’ This is associated with deficient resolution of alveolar neutrophilia similar to that seen in Lxr-null mice, and is associated with defects in macrophage-mediated efferocytosis, TGFb induction, and recruitment of Tregs to the airway. Ch25h is induced in macrophages during efferocytosis, and Ch25h-null efferocytic macrophages display defective LXR activation, failing to induce the LXR target gene and efferocytosis receptor Mertk. We show that resolution in Ch25h-null mice is rescued by treatment with either 25HC or synthetic LXR agonists. Suggesting a potential class effect of LXR-active oxysterols in resolution of inflammation, we also show that human alveolar macrophages synthesize the oxysterol cholestenoic acid and that, in acute lung injury patients, plasma cholestenoic acid is inversely related to pro-inflammatory biomarkers and duration of organ failure. Taken together, oxysterols are bioactive lipids that play a key protective role through coordinate promotion of lipid and inflammatory homeostasis. We propose that these insights have potential therapeutic relevance to human lung disease.

NLM Title:	Novel roles for oxysterols in resolution of inflammation and critical illness / Michael B. Fessler ; Immunology Interest Group.
Author:	Fessler, Michael B. National Institutes of Health (U.S.). Immunology Interest Group,
Publisher:
Abstract:	(CIT): Michael Fessler is a physician scientist who is a Senior Investigator and Deputy Chief of the Immunity, Inflammation, and Disease Laboratory of the intramural research program at NIEHS/NIH. Mike received his M.D. at Harvard Medical School in 1996, after which he completed an internal medicine residency at Massachusetts General Hospital from 1996-1999, and then a pulmonary-critical care fellowship at University of Colorado from 1999-2002. In 2006, after four years on faculty at National Jewish Hospital, Mike started as a Tenure Track Investigator at NIEHS, and, in 2013, he received tenure. His laboratory focuses on the innate immune response, with a particular interest in mechanisms by which cholesterol trafficking through macrophages and the lung regulates host defense. His laboratory has helped to define the role of cholesterol transporters in regulation of lung inflammation and immunity, the role of lipid rafts in TLR signaling, and the therapeutic potential of statins and Liver X Receptor agonists in preclinical models of lung disease. In 2012, Mike received the Carol Basbaum Award from the American Thoracic Society, and in 2015 was inducted into the American Society for Clinical Investigation. Talk Abstract: Recent reports have revealed there to be substantial steady state flux of cholesterol through the lung, and have interestingly indicated that cholesterol trafficking may be uniquely coupled to immune and inflammatory responses in this organ. The oxysterol-activated nuclear receptor, Liver X Receptor (LXR), is in particular positioned at the crossroads of lipid homeostasis and immunity as it coordinately promotes cellular cholesterol mobilization and suppresses NF-[kappa]B-dependent inflammation. Here, we identify cholesterol-25-hydroxylase (Ch25h)-derived 25-hydroxycholesterol (25HC) as a lipopolysaccharide (LPS)-induced oxysterol that is uniquely required for promoting LXR-dependent resolution of inflammation in the lung. LPS inhalation upregulates Ch25h in pulmonary macrophages, inducing 25HC in the murine and human airspace in vivo. Ch25h-null mice do not induce 25HC after LPS and display abrogated activation of LXR in the lungs and accumulation of lipid-laden macrophage "foam cells." This is associated with deficient resolution of alveolar neutrophilia similar to that seen in Lxr-null mice, and is associated with defects in macrophage-mediated efferocytosis, TGFb induction, and recruitment of Tregs to the airway. Ch25h is induced in macrophages during efferocytosis, and Ch25h-null efferocytic macrophages display defective LXR activation, failing to induce the LXR target gene and efferocytosis receptor Mertk. We show that resolution in Ch25h-null mice is rescued by treatment with either 25HC or synthetic LXR agonists. Suggesting a potential class effect of LXR-active oxysterols in resolution of inflammation, we also show that human alveolar macrophages synthesize the oxysterol cholestenoic acid and that, in acute lung injury patients, plasma cholestenoic acid is inversely related to pro-inflammatory biomarkers and duration of organ failure. Taken together, oxysterols are bioactive lipids that play a key protective role through coordinate promotion of lipid and inflammatory homeostasis. We propose that these insights have potential therapeutic relevance to human lung disease.
Subjects:	Cholesterol--immunology Inflammation Lung--immunology
Publication Types:	Lecture Webcast

NLM Classification:	QU 95
NLM ID:	101676596
CIT Live ID:	18285
Permanent link:	https://videocast.nih.gov/watch=18285

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