A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress

Sara Perrotta; Lorenzo Carnevale; Marialuisa Perrotta; Fabio Pallante; Tomasz P Mikołajczyk; Valentina Fardella; Agnese Migliaccio; Stefania Fardella; Sara Nejat; Boguslaw Kapelak; Azzurra Zonfrilli; Jacopo Pacella; Francesco Mastroiacovo; Raimondo Carnevale; Calum Bain; Sarah Lena Puhl; Giuseppe D'Agostino; Slava Epelman; Tomasz J Guzik; Giuseppe Lembo; Daniela Carnevale

doi:10.1016/j.immuni.2025.02.013

A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress

Sara Perrotta, Lorenzo Carnevale, Marialuisa Perrotta, Fabio Pallante, Tomasz P Mikołajczyk, Valentina Fardella, Agnese Migliaccio, Stefania Fardella, Sara Nejat, Boguslaw Kapelak, Azzurra Zonfrilli, Jacopo Pacella, Francesco Mastroiacovo, Raimondo Carnevale, Calum Bain, Sarah Lena Puhl, Giuseppe D'Agostino, Slava Epelman, Tomasz J Guzik, Giuseppe LemboDaniela Carnevale

Research output: Contribution to journal › Article › peer-review

Abstract

Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. We report that LV pressure overload recruited a brainstem neural circuit to enhance splenic SNS and induce placental growth factor (PlGF) secretion. During hypertensive stress, PlGF drove the proliferation of self-renewing cardiac resident macrophages (RMs) expressing its receptor neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to HF. In humans, circulating PlGF correlated with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs. Here, we discovered a multiorgan response driving a neural reflex to expand cardiac NRP1+ RM and counteract HF.

Original language	English
Pages (from-to)	648-665.e7
Journal	Immunity
Volume	58
Issue number	3
Early online date	28 Feb 2025
DOIs	https://doi.org/10.1016/j.immuni.2025.02.013
Publication status	Published - 11 Mar 2025

Keywords / Materials (for Non-textual outputs)

Animals
Brain/metabolism
Heart Failure/metabolism
Heart/physiopathology
Humans
Hypertension/metabolism
Macrophages/metabolism
Male
Mice
Mice, Inbred C57BL
Neuropilin-1/metabolism
Placenta Growth Factor/metabolism
Spleen/metabolism
Sympathetic Nervous System/metabolism
Ventricular Remodeling
heart failure
autonomic nervous system
neuropilin-1 macrophages
cardiac pressure overload
neuroimmune interactions
hypertension

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10.1016/j.immuni.2025.02.013Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Carnevale_v 09 feb 25_final_Calum BainAccepted author manuscript, 324 KB
1-s2.0-S1074761325000809-mainFinal published version, 7.73 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

Investigating the role of TGF Beta in the functional imprinting of pulmonary macrophages in health and disease
Bain, C. (Principal Investigator)
Royal Society
1/09/17 → 31/12/23
Project: Research

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Perrotta, S., Carnevale, L., Perrotta, M., Pallante, F., Mikołajczyk, T. P., Fardella, V., Migliaccio, A., Fardella, S., Nejat, S., Kapelak, B., Zonfrilli, A., Pacella, J., Mastroiacovo, F., Carnevale, R., Bain, C., Puhl, S. L., D'Agostino, G., Epelman, S., Guzik, T. J., ... Carnevale, D. (2025). A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress. Immunity, 58(3), 648-665.e7. https://doi.org/10.1016/j.immuni.2025.02.013

@article{42dd21c5d5d545158ec3de1ced1eb772,

title = "A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress",

abstract = "Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. We report that LV pressure overload recruited a brainstem neural circuit to enhance splenic SNS and induce placental growth factor (PlGF) secretion. During hypertensive stress, PlGF drove the proliferation of self-renewing cardiac resident macrophages (RMs) expressing its receptor neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to HF. In humans, circulating PlGF correlated with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs. Here, we discovered a multiorgan response driving a neural reflex to expand cardiac NRP1+ RM and counteract HF.",

keywords = "Animals, Brain/metabolism, Heart Failure/metabolism, Heart/physiopathology, Humans, Hypertension/metabolism, Macrophages/metabolism, Male, Mice, Mice, Inbred C57BL, Neuropilin-1/metabolism, Placenta Growth Factor/metabolism, Spleen/metabolism, Sympathetic Nervous System/metabolism, Ventricular Remodeling, heart failure, autonomic nervous system, neuropilin-1 macrophages, cardiac pressure overload, neuroimmune interactions, hypertension",

author = "Sara Perrotta and Lorenzo Carnevale and Marialuisa Perrotta and Fabio Pallante and Miko{\l}ajczyk, {Tomasz P} and Valentina Fardella and Agnese Migliaccio and Stefania Fardella and Sara Nejat and Boguslaw Kapelak and Azzurra Zonfrilli and Jacopo Pacella and Francesco Mastroiacovo and Raimondo Carnevale and Calum Bain and Puhl, {Sarah Lena} and Giuseppe D'Agostino and Slava Epelman and Guzik, {Tomasz J} and Giuseppe Lembo and Daniela Carnevale",

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doi = "10.1016/j.immuni.2025.02.013",

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Perrotta, S, Carnevale, L, Perrotta, M, Pallante, F, Mikołajczyk, TP, Fardella, V, Migliaccio, A, Fardella, S, Nejat, S, Kapelak, B, Zonfrilli, A, Pacella, J, Mastroiacovo, F, Carnevale, R, Bain, C, Puhl, SL, D'Agostino, G, Epelman, S, Guzik, TJ, Lembo, G & Carnevale, D 2025, 'A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress', Immunity, vol. 58, no. 3, pp. 648-665.e7. https://doi.org/10.1016/j.immuni.2025.02.013

TY - JOUR

T1 - A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress

AU - Perrotta, Sara

AU - Carnevale, Lorenzo

AU - Perrotta, Marialuisa

AU - Pallante, Fabio

AU - Mikołajczyk, Tomasz P

AU - Fardella, Valentina

AU - Migliaccio, Agnese

AU - Fardella, Stefania

AU - Nejat, Sara

AU - Kapelak, Boguslaw

AU - Zonfrilli, Azzurra

AU - Pacella, Jacopo

AU - Mastroiacovo, Francesco

AU - Carnevale, Raimondo

AU - Bain, Calum

AU - Puhl, Sarah Lena

AU - D'Agostino, Giuseppe

AU - Epelman, Slava

AU - Guzik, Tomasz J

AU - Lembo, Giuseppe

AU - Carnevale, Daniela

PY - 2025/3/11

Y1 - 2025/3/11

N2 - Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. We report that LV pressure overload recruited a brainstem neural circuit to enhance splenic SNS and induce placental growth factor (PlGF) secretion. During hypertensive stress, PlGF drove the proliferation of self-renewing cardiac resident macrophages (RMs) expressing its receptor neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to HF. In humans, circulating PlGF correlated with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs. Here, we discovered a multiorgan response driving a neural reflex to expand cardiac NRP1+ RM and counteract HF.

AB - Hypertensive heart disease (HTN-HD) meaningfully contributes to hypertension morbidity and mortality. Initially established as an adaptive response, HTN-HD progresses toward worsening of left ventricule (LV) function and heart failure (HF). Hypertensive stress elevates sympathetic nervous system (SNS) activity, a negative clinical predictor, and expands macrophages. How they interact in the compensatory phase of HTN-HD is unclear. We report that LV pressure overload recruited a brainstem neural circuit to enhance splenic SNS and induce placental growth factor (PlGF) secretion. During hypertensive stress, PlGF drove the proliferation of self-renewing cardiac resident macrophages (RMs) expressing its receptor neuropilin-1 (NRP1). Inhibition of the splenic neuroimmune axis or ablation of NRP1 in RM hindered the adaptive response to hypertensive stress, leading to HF. In humans, circulating PlGF correlated with cardiac hypertrophy, and failing hearts expressed NRP1 in RMs. Here, we discovered a multiorgan response driving a neural reflex to expand cardiac NRP1+ RM and counteract HF.

KW - Animals

KW - Brain/metabolism

KW - Heart Failure/metabolism

KW - Heart/physiopathology

KW - Humans

KW - Hypertension/metabolism

KW - Macrophages/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Neuropilin-1/metabolism

KW - Placenta Growth Factor/metabolism

KW - Spleen/metabolism

KW - Sympathetic Nervous System/metabolism

KW - Ventricular Remodeling

KW - heart failure

KW - autonomic nervous system

KW - neuropilin-1 macrophages

KW - cardiac pressure overload

KW - neuroimmune interactions

KW - hypertension

U2 - 10.1016/j.immuni.2025.02.013

DO - 10.1016/j.immuni.2025.02.013

M3 - Article

C2 - 40023160

SN - 1074-7613

VL - 58

SP - 648-665.e7

JO - Immunity

JF - Immunity

IS - 3

ER -

A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress

Abstract

Keywords / Materials (for Non-textual outputs)

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Projects

Investigating the role of TGF Beta in the functional imprinting of pulmonary macrophages in health and disease

Cite this