A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model
Background and AimsThe mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution o...
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doaj-3863b01737194265bbe2e1630ed5eee32020-12-16T05:53:41ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-12-011110.3389/fimmu.2020.563434563434A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse ModelNatalia Muñoz-Durango0Marco Arrese1Marco Arrese2Alejandra Hernández3Evelyn Jara4Evelyn Jara5Alexis M. Kalergis6Alexis M. Kalergis7Daniel Cabrera8Daniel Cabrera9Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileDepartamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, ChileCentro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileDepartamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, ChileMillennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileDepartamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Santiago, ChileMillennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, ChileDepartamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, ChileDepartamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, ChileFacultad de Ciencias Médicas, Universidad Bernardo O Higgins, Santiago, ChileBackground and AimsThe mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD).MethodsMice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development.ResultsMyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8+ T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8+ T cells were significantly reduced in MyMRKO.ConclusionsProinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis.https://www.frontiersin.org/articles/10.3389/fimmu.2020.563434/fullnon-alcoholic steatohepatitissteatohepatitisfatty liverinflammationfibrosismineralocorticoid receptor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Natalia Muñoz-Durango Marco Arrese Marco Arrese Alejandra Hernández Evelyn Jara Evelyn Jara Alexis M. Kalergis Alexis M. Kalergis Daniel Cabrera Daniel Cabrera |
spellingShingle |
Natalia Muñoz-Durango Marco Arrese Marco Arrese Alejandra Hernández Evelyn Jara Evelyn Jara Alexis M. Kalergis Alexis M. Kalergis Daniel Cabrera Daniel Cabrera A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model Frontiers in Immunology non-alcoholic steatohepatitis steatohepatitis fatty liver inflammation fibrosis mineralocorticoid receptor |
author_facet |
Natalia Muñoz-Durango Marco Arrese Marco Arrese Alejandra Hernández Evelyn Jara Evelyn Jara Alexis M. Kalergis Alexis M. Kalergis Daniel Cabrera Daniel Cabrera |
author_sort |
Natalia Muñoz-Durango |
title |
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model |
title_short |
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model |
title_full |
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model |
title_fullStr |
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model |
title_full_unstemmed |
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model |
title_sort |
mineralocorticoid receptor deficiency in myeloid cells reduces liver steatosis by impairing activation of cd8+ t cells in a nonalcoholic steatohepatitis mouse model |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-12-01 |
description |
Background and AimsThe mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD).MethodsMice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development.ResultsMyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8+ T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8+ T cells were significantly reduced in MyMRKO.ConclusionsProinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis. |
topic |
non-alcoholic steatohepatitis steatohepatitis fatty liver inflammation fibrosis mineralocorticoid receptor |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.563434/full |
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