Modulation of chronic inflammation by the mineralocorticoid receptor during experimental autoimmune encephalomyelitis.
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1
Pontificia Universidad Católica de Chile, Millennium Institute on Immunology and Immunotherapy. Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile., Chile
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2
Pontificia Universidad Católica de Chile, Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile., Chile
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3
Universidad Andrés Bello, Millennium Institute on Immunology and Immunotherapy. Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Medicina Universidad Andrés Bello., Chile
The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been conventionally related with the control of water and electrolyte homeostasis to keep blood pressure through aldosterone activation. However, MR expression is not restricted to vascular and renal tissue, as it has been shown in cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. Furthermore, aldosterone has been associated to pro-inflammatory immune effects, such as the release of cytokines that promote oxidative stress and fibrosis. The inflammatory contribution of MR and aldosterone to cardiovascular diseases is supported by the observation that hypertensive patients show higher levels of pro-inflammatory mediators, which can be modulated by antagonizing MR. The molecular and cellular mechanisms that mediate the inflammatory effects of MR and aldosterone remain unknown.
We have shown that dendritic cells (DCs) express and respond to MR stimulation with aldosterone by secreting pro-inflammatory cytokines, such as IL-6 and TGF-β. These molecules induce the polarization of the adaptive immune response toward a Th17 phenotype, which enhances autoimmune diseases. Furthermore, MR antagonism with spironolactone in hypertension rat model reduced end-organ damage due to blockade of Th17 polarization and the induction of T regulatory cells. To further elucidate the contribution of MR to the immune response, we studied MR conditional knockout mice, in which only myeloid cells do not express MR (MyMRKO). We observed that MyMRKO mice developed higher clinical EAE scores, as compared to wild type litter mate mice. In addition, MyMRKO mice showed a higher percentage of CD45+ leukocytes infiltrating the central nervous system (CNS). Further, the percentage of CD45+CD8+ lymphocytes was significantly higher in CNS of MyMRKO mice as compared to control animals. Although the percentage of CD45+CD4+ infiltrating cells was not different between MyMRKO and control mice, approximately 90% of these cells from MyMRKO were also CD25+, suggesting a differential modulation of T cell response in MyMRKO. In vitro co-cultures consisting on DCs derived from wild type litter mate or MyMRKO and CD4+ or CD8+ T cells, showed a higher levels of IL-17A and IFN-γ secretion from CD8+ cells derived from MyMRKO mice. In conclusion, our data suggest that MR receptor could be important to modulate the CD8+ T cell responses during EAE.
Acknowledgements
Acknowledgment
The authors are supported by grants FONDECYT nº 1110397, 1130427, 1131012, 1130996, 3150559, IMII P09/016-F. NMD and LV are CONICYT fellows.
References
Keywords:
mineralocorticoid receptor,
Aldosterone Antagonists,
Inflammation,
Encephalomyelitis, Autoimmune, Experimental,
T cell polarization
Conference:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.
Presentation Type:
Poster Presentation
Topic:
Innate Immunity
Citation:
Munoz Durango
N,
Becerra Diedrichs
D,
Jara Fernández
EL,
Kalergis
AM,
Riedel
CA,
Albornoz
E and
Venegas
L
(2015). Modulation of chronic inflammation by the mineralocorticoid receptor during experimental autoimmune encephalomyelitis..
Front. Immunol.
Conference Abstract:
IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología.
doi: 10.3389/conf.fimmu.2015.05.00031
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Received:
05 May 2015;
Published Online:
14 Sep 2015.
*
Correspondence:
Dr. Alexis M Kalergis, Pontificia Universidad Católica de Chile, Millennium Institute on Immunology and Immunotherapy. Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile., Santiago de Chile, Región Metropolitana, 8320000, Chile, akalergis@bio.puc.cl