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Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus

To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected...

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Autores principales: Kingsmore, Kathryn M., Bachali, Prathyusha, Catalina, Michelle D., Daamen, Andrea R., Heuer, Sarah E., Robl, Robert D., Grammer, Amrie C., Lipsky, Peter E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292402/
https://www.ncbi.nlm.nih.gov/pubmed/34285256
http://dx.doi.org/10.1038/s41598-021-93034-w
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author Kingsmore, Kathryn M.
Bachali, Prathyusha
Catalina, Michelle D.
Daamen, Andrea R.
Heuer, Sarah E.
Robl, Robert D.
Grammer, Amrie C.
Lipsky, Peter E.
author_facet Kingsmore, Kathryn M.
Bachali, Prathyusha
Catalina, Michelle D.
Daamen, Andrea R.
Heuer, Sarah E.
Robl, Robert D.
Grammer, Amrie C.
Lipsky, Peter E.
author_sort Kingsmore, Kathryn M.
collection PubMed
description To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected skin and kidney. Regression models in DLE indicated increased glycolysis was correlated with keratinocyte, endothelial, and inflammatory cell transcripts, and decreased tricarboxylic (TCA) cycle genes were correlated with the keratinocyte signature. In LN, regression models demonstrated decreased glycolysis and TCA cycle genes were correlated with increased endothelial or decreased kidney cell transcripts, respectively. Less severe glomerular LN exhibited similar alterations in metabolism and tissue cell transcripts before monocyte/myeloid cell infiltration in some patients. Additionally, changes to mitochondrial and peroxisomal transcripts were associated with specific cells rather than global signal changes. Examination of murine LN gene expression demonstrated metabolic changes were not driven by acute exposure to type I interferon and could be restored after immunosuppression. Finally, expression of HAVCR1, a tubule damage marker, was negatively correlated with the TCA cycle signature in LN models. These results indicate that altered metabolic dysfunction is a common, reversible change in lupus-affected tissues and appears to reflect damage downstream of immunologic processes.
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spelling pubmed-82924022021-07-22 Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus Kingsmore, Kathryn M. Bachali, Prathyusha Catalina, Michelle D. Daamen, Andrea R. Heuer, Sarah E. Robl, Robert D. Grammer, Amrie C. Lipsky, Peter E. Sci Rep Article To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected skin and kidney. Regression models in DLE indicated increased glycolysis was correlated with keratinocyte, endothelial, and inflammatory cell transcripts, and decreased tricarboxylic (TCA) cycle genes were correlated with the keratinocyte signature. In LN, regression models demonstrated decreased glycolysis and TCA cycle genes were correlated with increased endothelial or decreased kidney cell transcripts, respectively. Less severe glomerular LN exhibited similar alterations in metabolism and tissue cell transcripts before monocyte/myeloid cell infiltration in some patients. Additionally, changes to mitochondrial and peroxisomal transcripts were associated with specific cells rather than global signal changes. Examination of murine LN gene expression demonstrated metabolic changes were not driven by acute exposure to type I interferon and could be restored after immunosuppression. Finally, expression of HAVCR1, a tubule damage marker, was negatively correlated with the TCA cycle signature in LN models. These results indicate that altered metabolic dysfunction is a common, reversible change in lupus-affected tissues and appears to reflect damage downstream of immunologic processes. Nature Publishing Group UK 2021-07-20 /pmc/articles/PMC8292402/ /pubmed/34285256 http://dx.doi.org/10.1038/s41598-021-93034-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kingsmore, Kathryn M.
Bachali, Prathyusha
Catalina, Michelle D.
Daamen, Andrea R.
Heuer, Sarah E.
Robl, Robert D.
Grammer, Amrie C.
Lipsky, Peter E.
Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title_full Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title_fullStr Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title_full_unstemmed Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title_short Altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
title_sort altered expression of genes controlling metabolism characterizes the tissue response to immune injury in lupus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292402/
https://www.ncbi.nlm.nih.gov/pubmed/34285256
http://dx.doi.org/10.1038/s41598-021-93034-w
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