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

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.; To aid visualization of cellular events orchestrating multi-organ pathogenesis, we modeled hypertensive cardiovascular remodeling in zebrafish. Zebrafish larvae exposed to ion-poor environment exhibited rapid angiotensinogen upregulation, followed by manifestation of arterial hypertension and cardiac remodeling 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 upregulation of interferon-γ and interleukin 1β, and revealed altered macrophage/microglia transcriptional program 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 signaling. In zebrafish, interferon-γ receptor 1 mutation prevents cerebrovascular remodeling and dysregulation of macrophage/microglia transcriptomic profile. Supplementation of bone morphogenetic protein 5, identified from the transcriptomic approach as a downregulated 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.; These findings uncover cellular and molecular players of an immune pathway communicating hypertensive stimulus to structural and functional remodeling 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.; Hypertension is a major risk factor for damages of the vasculature, heart, and brain, and thereby a major healthcare burden. Inadequate cerebral blood supply due to altered cerebrovascular structure and vasoregulatory disruption upon hypertension render the brain highly susceptible to stroke and cognitive decline. We envision that the cellular and molecular mechanisms uncovered here linking immune dysregulation to cerebrovascular remodeling and functional impairment of the brain will inform future development of immunomodulatory therapeutic strategies for counteracting derangement of macrophage/microglia activation and their vasculo/neuroprotective function in response to systemic inflammation in hypertension.