Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with an estimated prevalence of 25%–30% in the general population [1, 2]
All experiments were performed with conditional knockout mice in which the expression of mineralocorticoid receptor (MR) was abolished in myeloid cells [26]
MR deletion-efficiency in bloodderived myeloid cells obtained from WT, flox as control mice (FC), and myleoid mineralocorticoide receptor (MyMRKO) mice was evaluated by qPCR
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with an estimated prevalence of 25%–30% in the general population [1, 2]. NAFLD is linked to obesity and occurs as a sequential process that starts with lipid accumulation (steatosis), followed by a local inflammatory response and injury, which fuels progression to fibrosis [3]. Purified and activated HSC can regulate the function of CD8+ T lymphocytes, which displayed lower proliferative index and cytotoxic activity [8]. This observation suggests an important link between these cell populations and the pathogenesis of liver fibrosis. The mineralocorticoid receptor (MR) and renin-angiotensinaldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). 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)
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