TY - JOUR
T1 - Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase-associated lipocalin expression upon mineralocorticoid receptor activation
AU - Araos, Patricio
AU - Prado, Carolina
AU - Lozano, Mauricio
AU - Figueroa, Stefanny
AU - Espinoza, Alexandra
AU - Berger, Thorsten
AU - Mak, Tak W.
AU - Jaisser, Frédéric
AU - Pacheco, Rodrigo
AU - Michea, Luis
AU - Amador, Cristián A.
N1 - Funding Information:
The work was supported by FONDECYT Iniciación 11150542 (C.A.A.), CONICYT-Doctorado 21130482 (P.A.), FONDECYT-Postdoctorado 3160383 (C.P.), FONDECYT-Regular grants 1130550 and 1171869 (L.M.), 1170093 (R.P.), CONICYT-Basal AFB 170004 (R.P.), The Millennium Institute on Immunology and Immunotherapy (MIII; P09/ 016-F ICM), Fondation de France (2014-00047968), ANR MRFOCUS (ANR-15-CE14-0032-02), and the Fight-HF Avenir investment program (ANR-15-RHUS-0004) (F.J.).
Publisher Copyright:
© 2019 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Background:Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown.Objective:We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation.Methods:Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment.Results:The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively.Conclusion:NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess.
AB - Background:Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown.Objective:We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation.Methods:Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment.Results:The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively.Conclusion:NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess.
KW - cardiovascular fibrosis
KW - dendritic cells
KW - inflammation
KW - mineralocorticoid receptor
KW - neutrophil gelatinase-associated lipocalin
UR - http://www.scopus.com/inward/record.url?scp=85067269649&partnerID=8YFLogxK
U2 - 10.1097/HJH.0000000000002067
DO - 10.1097/HJH.0000000000002067
M3 - Article
C2 - 31033725
AN - SCOPUS:85067269649
SN - 0263-6352
VL - 37
SP - 1482
EP - 1492
JO - Journal of Hypertension
JF - Journal of Hypertension
IS - 7
ER -