Interferon-γ drives macrophage reprogramming, cerebrovascular remodelling, and cognitive dysfunction in a zebrafish and a mouse model of ion imbalance and pressure overload

Author:

Apaydin Dilem C12,Zakarauskas-Seth Bhakti I13,Carnevale Lorenzo4ORCID,Apaydin Onur12,Perrotta Marialuisa45,Carnevale Raimondo4ORCID,Kotini Maria P6,Kotlar-Goldaper Ilan13,Belting Heinz-Georg6,Carnevale Daniela45ORCID,Filosa Alessandro1,Sawamiphak Suphansa17ORCID

Affiliation:

1. Max Delbrück Center (MDC) , Robert-Rössle-Str. 10, 13125 Berlin , Germany

2. Institute of Chemistry and Biochemistry, Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin , Berlin , Germany

3. Charité—Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin , Berlin , Germany

4. Unit of Neuro and Cardiovascular Pathophysiology, IRCCS Neuromed , Pozzilli (Isernia) , Italy

5. Department of Molecular Medicine, Sapienza University of Rome , Rome , Italy

6. Department of Cell Biology, Biozentrum, University of Basel , Basel , Switzerland

7. DZHK (German Center for Cardiovascular Research), Partner Site Berlin , GeschäftsstellePotsdamer Str. 58, 10785 Berlin , Germany

Abstract

Abstract Aims Dysregulated immune response contributes to inefficiency of treatment strategies to control hypertension and reduce the risk of end-organ damage. Uncovering the immune pathways driving the transition from the onset of hypertensive stimulus to the manifestation of multi-organ dysfunction are much-needed insights for immune targeted therapy. Methods and results To aid visualization of cellular events orchestrating multi-organ pathogenesis, we modelled hypertensive cardiovascular remodelling in zebrafish. Zebrafish larvae exposed to ion-poor environment exhibited rapid angiotensinogen up-regulation, followed by manifestation of arterial hypertension and cardiac remodelling that recapitulates key characteristics of incipient heart failure with preserved ejection fraction. In the brain, time-lapse imaging revealed the occurrence of cerebrovascular regression through endothelial retraction and migration in response to the ion-poor treatment. This phenomenon is associated with macrophage/microglia-endothelial contacts and endothelial junctional retraction. Cytokine and transcriptomic profiling identified systemic up-regulation of interferon-γ and interleukin 1β and revealed altered macrophage/microglia transcriptional programme characterized by suppression of innate immunity and vasculo/neuroprotective gene expression. Both zebrafish and a murine model of pressure overload-induced brain damage demonstrated that the brain pathology and macrophage/microglia phenotypic alteration are dependent on interferon-γ signalling. In zebrafish, interferon-γ receptor 1 mutation prevents cerebrovascular remodelling and dysregulation of macrophage/microglia transcriptomic profile. Supplementation of bone morphogenetic protein 5 identified from the transcriptomic approach as a down-regulated gene in ion-poor-treated macrophages/microglia that is rescued by interferon-γ blockage, mitigated cerebral microvessel loss. In mice subjected to transverse aortic constriction-induced pressure overload, typically developing cerebrovascular injury, neuroinflammation, and cognitive dysfunction, interferon-γ neutralization protected them from blood–brain barrier disruption, cerebrovascular rarefaction, and cognitive decline. Conclusions These findings uncover cellular and molecular players of an immune pathway communicating hypertensive stimulus to structural and functional remodelling of the brain and identify anti-interferon-γ treatment as a promising intervention strategy capable of preventing pressure overload-induced damage of the cerebrovascular and nervous systems.

Funder

Helmholtz Association of German Research Centers

Deutsche Forschungsgemeinschaft

DFG, German Research Foundation

German Federal Ministry of Education and Research

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

Reference70 articles.

1. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical Pr;Whelton;Hypertension,2018

2. Animal models of hypertension: a scientific statement from the American heart association;Lerman;Hypertens (Dallas, Tex 1979),2019

3. Immune mechanisms of hypertension;Drummond;Nat Rev Immunol,2019

4. Novel immune mechanisms in hypertension and cardiovascular risk;Nosalski;Curr Cardiovasc Risk Rep,2017

5. Group on behalf of the PS. Residual cardiovascular risk in treated hypertension and hyperlipidaemia: the PRIME study;Blacher;J Hum Hypertens,2010

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3