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Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology

Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (D...

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Autores principales: Mazzarino, Morgane, Cetin, Esra, Bartosova, Maria, Marinovic, Iva, Ipseiz, Natacha, Hughes, Timothy R., Schmitt, Claus Peter, Ramji, Dipak P., Labéta, Mario O., Raby, Anne-Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577224/
https://www.ncbi.nlm.nih.gov/pubmed/37849759
http://dx.doi.org/10.3389/fimmu.2023.1240679
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author Mazzarino, Morgane
Cetin, Esra
Bartosova, Maria
Marinovic, Iva
Ipseiz, Natacha
Hughes, Timothy R.
Schmitt, Claus Peter
Ramji, Dipak P.
Labéta, Mario O.
Raby, Anne-Catherine
author_facet Mazzarino, Morgane
Cetin, Esra
Bartosova, Maria
Marinovic, Iva
Ipseiz, Natacha
Hughes, Timothy R.
Schmitt, Claus Peter
Ramji, Dipak P.
Labéta, Mario O.
Raby, Anne-Catherine
author_sort Mazzarino, Morgane
collection PubMed
description Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients’ plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients’ plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD.
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spelling pubmed-105772242023-10-17 Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology Mazzarino, Morgane Cetin, Esra Bartosova, Maria Marinovic, Iva Ipseiz, Natacha Hughes, Timothy R. Schmitt, Claus Peter Ramji, Dipak P. Labéta, Mario O. Raby, Anne-Catherine Front Immunol Immunology Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. Chronic inflammation, a hallmark of both CKD and CV diseases (CVD), is believed to drive this association. Pro-inflammatory endogenous TLR agonists, Damage-Associated Molecular Patterns (DAMPs), have been found elevated in CKD patients’ plasma and suggested to promote CVD, however, confirmation of their involvement, the underlying mechanism(s), the extent to which individual DAMPs contribute to vascular pathology in CKD and the evaluation of potential therapeutic strategies, have remained largely undescribed. A multi-TLR inhibitor, soluble TLR2, abrogated chronic vascular inflammatory responses and the increased aortic atherosclerosis-associated gene expression observed in nephropathic mice, without compromising infection clearance. Mechanistically, we confirmed elevation of 4 TLR DAMPs in CKD patients’ plasma, namely Hsp70, Hyaluronic acid, HMGB-1 and Calprotectin, which displayed different abilities to promote key cellular responses associated with vascular inflammation and progression of atherosclerosis in a TLR-dependent manner. These included loss of trans-endothelial resistance, enhanced monocyte migration, increased cytokine production, and foam cell formation by macrophages, the latter via cholesterol efflux inhibition. Calprotectin and Hsp70 most consistently affected these functions. Calprotectin was further elevated in CVD-diagnosed CKD patients and strongly correlated with the predictor of CV events CRP. In nephropathic mice, Calprotectin blockade robustly reduced vascular chronic inflammatory responses and pro-atherosclerotic gene expression in the blood and aorta. Taken together, these findings demonstrated the critical extent to which the DAMP-TLR pathway contributes to vascular inflammatory and atherogenic responses in CKD, revealed the mechanistic contribution of specific DAMPs and described two alternatives therapeutic approaches to reduce chronic vascular inflammation and lower CV pathology in CKD. Frontiers Media S.A. 2023-10-02 /pmc/articles/PMC10577224/ /pubmed/37849759 http://dx.doi.org/10.3389/fimmu.2023.1240679 Text en Copyright © 2023 Mazzarino, Cetin, Bartosova, Marinovic, Ipseiz, Hughes, Schmitt, Ramji, Labéta and Raby https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Mazzarino, Morgane
Cetin, Esra
Bartosova, Maria
Marinovic, Iva
Ipseiz, Natacha
Hughes, Timothy R.
Schmitt, Claus Peter
Ramji, Dipak P.
Labéta, Mario O.
Raby, Anne-Catherine
Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title_full Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title_fullStr Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title_full_unstemmed Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title_short Therapeutic targeting of chronic kidney disease-associated DAMPs differentially contributing to vascular pathology
title_sort therapeutic targeting of chronic kidney disease-associated damps differentially contributing to vascular pathology
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577224/
https://www.ncbi.nlm.nih.gov/pubmed/37849759
http://dx.doi.org/10.3389/fimmu.2023.1240679
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