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Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice
Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997930/ https://www.ncbi.nlm.nih.gov/pubmed/33772096 http://dx.doi.org/10.1038/s42003-021-01925-5 |
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author | Voisin, Maud Shrestha, Elina Rollet, Claire Nikain, Cyrus A. Josefs, Tatjana Mahé, Mélanie Barrett, Tessa J. Chang, Hye Rim Ruoff, Rachel Schneider, Jeffrey A. Garabedian, Michela L. Zoumadakis, Chris Yun, Chi Badwan, Bara Brown, Emily J. Mar, Adam C. Schneider, Robert J. Goldberg, Ira J. Pineda-Torra, Inés Fisher, Edward A. Garabedian, Michael J. |
author_facet | Voisin, Maud Shrestha, Elina Rollet, Claire Nikain, Cyrus A. Josefs, Tatjana Mahé, Mélanie Barrett, Tessa J. Chang, Hye Rim Ruoff, Rachel Schneider, Jeffrey A. Garabedian, Michela L. Zoumadakis, Chris Yun, Chi Badwan, Bara Brown, Emily J. Mar, Adam C. Schneider, Robert J. Goldberg, Ira J. Pineda-Torra, Inés Fisher, Edward A. Garabedian, Michael J. |
author_sort | Voisin, Maud |
collection | PubMed |
description | Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr(−/−) mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68(+) and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68(+) upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype. |
format | Online Article Text |
id | pubmed-7997930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79979302021-04-16 Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice Voisin, Maud Shrestha, Elina Rollet, Claire Nikain, Cyrus A. Josefs, Tatjana Mahé, Mélanie Barrett, Tessa J. Chang, Hye Rim Ruoff, Rachel Schneider, Jeffrey A. Garabedian, Michela L. Zoumadakis, Chris Yun, Chi Badwan, Bara Brown, Emily J. Mar, Adam C. Schneider, Robert J. Goldberg, Ira J. Pineda-Torra, Inés Fisher, Edward A. Garabedian, Michael J. Commun Biol Article Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr(−/−) mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68(+) and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68(+) upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype. Nature Publishing Group UK 2021-03-26 /pmc/articles/PMC7997930/ /pubmed/33772096 http://dx.doi.org/10.1038/s42003-021-01925-5 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Voisin, Maud Shrestha, Elina Rollet, Claire Nikain, Cyrus A. Josefs, Tatjana Mahé, Mélanie Barrett, Tessa J. Chang, Hye Rim Ruoff, Rachel Schneider, Jeffrey A. Garabedian, Michela L. Zoumadakis, Chris Yun, Chi Badwan, Bara Brown, Emily J. Mar, Adam C. Schneider, Robert J. Goldberg, Ira J. Pineda-Torra, Inés Fisher, Edward A. Garabedian, Michael J. Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title | Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title_full | Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title_fullStr | Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title_full_unstemmed | Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title_short | Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
title_sort | inhibiting lxrα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997930/ https://www.ncbi.nlm.nih.gov/pubmed/33772096 http://dx.doi.org/10.1038/s42003-021-01925-5 |
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