Unraveling the immune function of mineralocorticoid receptor (MR) and aldosterone in animal models.
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2019
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Abstract
Inflammation is a physiological response that could be triggered by endogenous and
exogenous stimulus. During inflammation the response is auto limited and regulated to keep
homeostasis, because uncontrolled response could lead to death. Inflammatory response is
complex and involves many systems of the body which crosstalk each with other. In this line,
hormones and its cognate receptors have been described as modulator of immune
response, for example glucocorticoids and its knowing immunosuppressive role have been
very useful to treat cancer and autoimmune diseases. Aldosterone is another adrenal
hormone, that under non-pathological condition controls renal excretion of water and
electrolytes to keep blood pressure. This hormone conventionally acts through
mineralocorticoid receptor (MR) which is a ligand dependent transcription factor mainly
expressed in juxtaglomerular epithelial cells in kidneys. However, MR is also expressed in
cells of the immune system, adipose tissue, liver and brain, indicating that could be paying
a role. Up to date, it has been described that high levels of aldosterone in vivo and in vitro
are related with the induction of inflammatory phenotype in cardiac diseases,
atherosclerosis, obesity, insulin resistance and autoimmunity.
Aimed to describe the immunological role in which MR and aldosterone are involved,
we used two models to study it. The first model was designed to understand whether MRaldosterone was related with TLR4 expression. According to our findings we described that
aldosterone via MR induces the expression of tlr4 in wild type (WT) bone marrow-derived
dendritic cells (DCs). Oppositely, the trl4 expression in DCs derived from myeloid MR
conditional knockout mice (MyMRKO) did not show to be modulated by aldosterone, indeed
these cells displayed impaired capacity to response to LPS stimulation. Finally, in a model
of sub-lethal endotoxemia, we found that mice pre-treated with aldosterone succumbs after
LPS challenge in contrast to placebo treated mice, mainly due to a multi-organic failure. In conclusion our results suggest that aldosterone-MR axis is involved in the regulation of tlr4
expression, and in consequently modulating the DCs response to TLR4 agonist, LPS.
Because the first model was focused in septic inflammation, the second model that
we used was focused in aseptic chronic inflammation in which MR and renin-angiotensinaldosterone system (RAAS) played a role. We induced non-alcoholic steatohepatitis (NASH)
in LM/WT and MyMRKO mice with methionine-choline deficient diet (MCD). We found that
MyMRKO mice fed with MCD diet presented lower lipid accumulation in livers than controls.
This finding was also related with lower number of CD8+ T lymphocytes infiltration in livers
of MyMRKO. This cells also displayed lower expression CD25 activation receptor, indicating
that antigen presenting cells (APC) derived from MyMRKO could be having impairments
promoting the immune response. In vitro cocultures performed with CD4+ or CD8+ T
lymphocytes plus DCs derived from MyMRKO mice displayed that only CD8+ response was
impaired and is related with the phenotype seen in mice.
Summarizing the results, we described that aldosterone through MR are involved in
tlr4 expression, because the loss of MR in myeloid DCs impacted in the levels of tlr4
expressed, indeed at basal condition. This result also affected the capacity of MyMRKO DCs
to sense and responds to LPS, which is a maturation stimulus, but in these cells failed to
induced a proinflammatory prone phenotype. These results are in accordance with the
lowest capacity of DCs to drive immune response of CD8+ T lymphocytes impacting in lower
steatosis in NASH model. In conclusion, all abovementioned results indicated that loss of
MR in myeloid cells impacts in the adaptive CD8+ immune response. However, further
analysis about how MR modulates antigen presenting cells to impair CD8+ T lymphocytes
function is needed.Inflammation is a physiological response that could be triggered by endogenous and
exogenous stimulus. During inflammation the response is auto limited and regulated to keep
homeostasis, because uncontrolled response could lead to death. Inflammatory response is
complex and involves many systems of the body which crosstalk each with other. In this line,
hormones and its cognate receptors have been described as modulator of immune
response, for example glucocorticoids and its knowing immunosuppressive role have been
very useful to treat cancer and autoimmune diseases. Aldosterone is another adrenal
hormone, that under non-pathological condition controls renal excretion of water and
electrolytes to keep blood pressure. This hormone conventionally acts through
mineralocorticoid receptor (MR) which is a ligand dependent transcription factor mainly
expressed in juxtaglomerular epithelial cells in kidneys. However, MR is also expressed in
cells of the immune system, adipose tissue, liver and brain, indicating that could be paying
a role. Up to date, it has been described that high levels of aldosterone in vivo and in vitro
are related with the induction of inflammatory phenotype in cardiac diseases,
atherosclerosis, obesity, insulin resistance and autoimmunity.
Aimed to describe the immunological role in which MR and aldosterone are involved,
we used two models to study it. The first model was designed to understand whether MRaldosterone was related with TLR4 expression. According to our findings we described that
aldosterone via MR induces the expression of tlr4 in wild type (WT) bone marrow-derived
dendritic cells (DCs). Oppositely, the trl4 expression in DCs derived from myeloid MR
conditional knockout mice (MyMRKO) did not show to be modulated by aldosterone, indeed
these cells displayed impaired capacity to response to LPS stimulation. Finally, in a model
of sub-lethal endotoxemia, we found that mice pre-treated with aldosterone succumbs after
LPS challenge in contrast to placebo treated mice, mainly due to a multi-organic failure. In conclusion our results suggest that aldosterone-MR axis is involved in the regulation of tlr4
expression, and in consequently modulating the DCs response to TLR4 agonist, LPS.
Because the first model was focused in septic inflammation, the second model that
we used was focused in aseptic chronic inflammation in which MR and renin-angiotensinaldosterone system (RAAS) played a role. We induced non-alcoholic steatohepatitis (NASH)
in LM/WT and MyMRKO mice with methionine-choline deficient diet (MCD). We found that
MyMRKO mice fed with MCD diet presented lower lipid accumulation in livers than controls.
This finding was also related with lower number of CD8+ T lymphocytes infiltration in livers
of MyMRKO. This cells also displayed lower expression CD25 activation receptor, indicating
that antigen presenting cells (APC) derived from MyMRKO could be having impairments
promoting the immune response. In vitro cocultures performed with CD4+ or CD8+ T
lymphocytes plus DCs derived from MyMRKO mice displayed that only CD8+ response was
impaired and is related with the phenotype seen in mice.
Summarizing the results, we described that aldosterone through MR are involved in
tlr4 expression, because the loss of MR in myeloid DCs impacted in the levels of tlr4
expressed, indeed at basal condition. This result also affected the capacity of MyMRKO DCs
to sense and responds to LPS, which is a maturation stimulus, but in these cells failed to
induced a proinflammatory prone phenotype. These results are in accordance with the
lowest capacity of DCs to drive immune response of CD8+ T lymphocytes impacting in lower
steatosis in NASH model. In conclusion, all abovementioned results indicated that loss of
MR in myeloid cells impacts in the adaptive CD8+ immune response. However, further
analysis about how MR modulates antigen presenting cells to impair CD8+ T lymphocytes
function is needed.Inflammation is a physiological response that could be triggered by endogenous and
exogenous stimulus. During inflammation the response is auto limited and regulated to keep
homeostasis, because uncontrolled response could lead to death. Inflammatory response is
complex and involves many systems of the body which crosstalk each with other. In this line,
hormones and its cognate receptors have been described as modulator of immune
response, for example glucocorticoids and its knowing immunosuppressive role have been
very useful to treat cancer and autoimmune diseases. Aldosterone is another adrenal
hormone, that under non-pathological condition controls renal excretion of water and
electrolytes to keep blood pressure. This hormone conventionally acts through
mineralocorticoid receptor (MR) which is a ligand dependent transcription factor mainly
expressed in juxtaglomerular epithelial cells in kidneys. However, MR is also expressed in
cells of the immune system, adipose tissue, liver and brain, indicating that could be paying
a role. Up to date, it has been described that high levels of aldosterone in vivo and in vitro
are related with the induction of inflammatory phenotype in cardiac diseases,
atherosclerosis, obesity, insulin resistance and autoimmunity.
Aimed to describe the immunological role in which MR and aldosterone are involved,
we used two models to study it. The first model was designed to understand whether MRaldosterone was related with TLR4 expression. According to our findings we described that
aldosterone via MR induces the expression of tlr4 in wild type (WT) bone marrow-derived
dendritic cells (DCs). Oppositely, the trl4 expression in DCs derived from myeloid MR
conditional knockout mice (MyMRKO) did not show to be modulated by aldosterone, indeed
these cells displayed impaired capacity to response to LPS stimulation. Finally, in a model
of sub-lethal endotoxemia, we found that mice pre-treated with aldosterone succumbs after
LPS challenge in contrast to placebo treated mice, mainly due to a multi-organic failure. In conclusion our results suggest that aldosterone-MR axis is involved in the regulation of tlr4
expression, and in consequently modulating the DCs response to TLR4 agonist, LPS.
Because the first model was focused in septic inflammation, the second model that
we used was focused in aseptic chronic inflammation in which MR and renin-angiotensinaldosterone system (RAAS) played a role. We induced non-alcoholic steatohepatitis (NASH)
in LM/WT and MyMRKO mice with methionine-choline deficient diet (MCD). We found that
MyMRKO mice fed with MCD diet presented lower lipid accumulation in livers than controls.
This finding was also related with lower number of CD8+ T lymphocytes infiltration in livers
of MyMRKO. This cells also displayed lower expression CD25 activation receptor, indicating
that antigen presenting cells (APC) derived from MyMRKO could be having impairments
promoting the immune response. In vitro cocultures performed with CD4+ or CD8+ T
lymphocytes plus DCs derived from MyMRKO mice displayed that only CD8+ response was
impaired and is related with the phenotype seen in mice.
Summarizing the results, we described that aldosterone through MR are involved in
tlr4 expression, because the loss of MR in myeloid DCs impacted in the levels of tlr4
expressed, indeed at basal condition. This result also affected the capacity of MyMRKO DCs
to sense and responds to LPS, which is a maturation stimulus, but in these cells failed to
induced a proinflammatory prone phenotype. These results are in accordance with the
lowest capacity of DCs to drive immune response of CD8+ T lymphocytes impacting in lower
steatosis in NASH model. In conclusion, all abovementioned results indicated that loss of
MR in myeloid cells impacts in the adaptive CD8+ immune response. However, further
analysis about how MR modulates antigen presenting cells to impair CD8+ T lymphocytes
function is needed.
Description
Tesis (Doctor en Ciencias Biológicas mención Genética Molecular y Microbiología)--Pontificia Universidad Católica de Chile, 2019