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In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXR\u03b1, LXR\u03b2) are ligand\u2010dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXR\u03b1 and LXR\u03b2 in antimicrobial responses. Here, the results demonstrate that induction of LXR\u03b1 transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXR\u03b1 transcription is induced by NF\u2010\u03baB and type\u2010I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXR\u03b1 cistrome that promotes cytokine and chemokine gene expression through direct LXR\u03b1 binding to DNA consensus sequences within cis\u2010regulatory regions including enhancers. LXR\u03b1\u2010deficient macrophages present fewer binding of p65 NF\u2010\u03baB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXR\u03b1 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\n                    <jats:sup>lo<\/jats:sup>\n                    \u2010MHC\u2010II\n                    <jats:sup>hi<\/jats:sup>\n                    peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXR\u03b1\u2010dependent transcriptional cis\u2010activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.\n                  <\/jats:p>","DOI":"10.1002\/advs.202307201","type":"journal-article","created":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:40:55Z","timestamp":1711672855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reprogramming of the LXR\u03b1 Transcriptome Sustains Macrophage Secondary Inflammatory Responses"],"prefix":"10.1002","volume":"11","author":[{"given":"Juan","family":"Vladimir de la Rosa","sequence":"first","affiliation":[{"name":"Unidad de Biomedicina (Unidad Asociada al CSIC) Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria  Las Palmas 35016 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Tabraue","sequence":"additional","affiliation":[{"name":"Unidad de Biomedicina (Unidad Asociada al CSIC) Instituto Universitario de Investigaciones Biom\u00e9dicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria  Las Palmas 35016 Spain"},{"name":"Departamento de Morfolog\u00eda Universidad de Las Palmas de Gran Canaria  Las Palmas 35016 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition Karolinska Institutet, NEO  Huddinge 14183 Sweden"},{"name":"Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine Medical School Nanjing University  Nanjing 210093 P. 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