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

  • Immunity. 2025 Mar 11;58(3):648-665.e7. doi: 10.1016/j.immuni.2025.02.013.
Sara Perrotta  1 ,  Lorenzo Carnevale  1 ,  Marialuisa Perrotta  2 ,  Fabio Pallante  1 ,  Tomasz P Mikołajczyk  3 ,  Valentina Fardella  1 ,  Agnese Migliaccio  1 ,  Stefania Fardella  1 ,  Sara Nejat  4 ,  Boguslaw Kapelak  5 ,  Azzurra Zonfrilli  6 ,  Jacopo Pacella  1 ,  Francesco Mastroiacovo  1 ,  Raimondo Carnevale  1 ,  Calum Bain  7 ,  Sarah Lena Puhl  8 ,  Giuseppe D'Agostino  9 ,  Slava Epelman  10 ,  Tomasz J Guzik  11 ,  Giuseppe Lembo  2 ,  Daniela Carnevale  12
Affiliations
  • 1. Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy.
  • 2. Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy; Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
  • 3. Department of Internal and Agricultural Medicine and Centre for Medical Genomics Omicron, Jagiellonian University, Collegium Medicum, Kraków, Poland.
  • 4. Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada.
  • 5. Department of Cardiac Surgery and Transplantation, Jagiellonian University, Collegium Medicum, Kraków, Poland.
  • 6. Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
  • 7. Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
  • 8. Comprehensive Heart Failure Center, Department of Translational Research, University Clinic Wuerzburg, Wuerzburg, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany.
  • 9. Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK.
  • 10. Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, ON, Canada; Ted Rogers Centre for Heart Research, Translational Biology and Engineering Program, Department of Immunology, University of Toronto, Peter Munk Cardiac Centre, UHN, Toronto, ON, Canada.
  • 11. Department of Internal and Agricultural Medicine and Centre for Medical Genomics Omicron, Jagiellonian University, Collegium Medicum, Kraków, Poland; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
  • 12. Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy; Department of Medical-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Latina, Italy. Electronic address: [email protected].
PMID: 40023160 DOI: 10.1016/j.immuni.2025.02.013
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
autonomic nervous system; cardiac pressure overload; heart failure; hypertension; neuroimmune interactions; neuropilin-1 macrophages.