Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.

Autor: Vladimir de la Rosa J; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, 35016, Spain., Tabraue C; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, 35016, Spain.; Departamento de Morfología, Universidad de Las Palmas de Gran Canaria, Las Palmas, 35016, Spain., Huang Z; Department of Biosciences and Nutrition, Karolinska Institutet, NEO, Huddinge, 14183, Sweden.; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, P. R. China., Orizaola MC; Department of Metabolic and Immune Diseases. Instituto de Investigaciones Biomédicas Sols-Morreale, Centro Mixto Consejo Superior de Investigaciones Científicas CSIC-Universidad Autónoma de Madrid, Madrid, 28029, Spain., Martin-Rodríguez P; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, 35016, Spain., Steffensen KR; Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Huddinge, 14186, Sweden., Zapata JM; Department of Metabolic and Immune Diseases. Instituto de Investigaciones Biomédicas Sols-Morreale, Centro Mixto Consejo Superior de Investigaciones Científicas CSIC-Universidad Autónoma de Madrid, Madrid, 28029, Spain., Boscá L; Department of Metabolic and Immune Diseases. Instituto de Investigaciones Biomédicas Sols-Morreale, Centro Mixto Consejo Superior de Investigaciones Científicas CSIC-Universidad Autónoma de Madrid, Madrid, 28029, Spain.; Centro de Investigación Biomedica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Madrid, 28029, Spain., Tontonoz P; Department of Pathology and Laboratory Medicine, University of California Los Angeles, UCLA, California, 90095, USA., Alemany S; Department of Metabolic and Immune Diseases. Instituto de Investigaciones Biomédicas Sols-Morreale, Centro Mixto Consejo Superior de Investigaciones Científicas CSIC-Universidad Autónoma de Madrid, Madrid, 28029, Spain., Treuter E; Department of Biosciences and Nutrition, Karolinska Institutet, NEO, Huddinge, 14183, Sweden., Castrillo A; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, 35016, Spain.; Department of Metabolic and Immune Diseases. Instituto de Investigaciones Biomédicas Sols-Morreale, Centro Mixto Consejo Superior de Investigaciones Científicas CSIC-Universidad Autónoma de Madrid, Madrid, 28029, Spain.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 May; Vol. 11 (20), pp. e2307201. Date of Electronic Publication: 2024 Mar 28.
DOI: 10.1002/advs.202307201
Abstrakt: Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80 lo -MHC-II hi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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