Neuroimmune cardiovascular interfaces control atherosclerosis

Sarajo K Mohanta*, Li Peng, Yuanfang Li, Shu Lu, Ting Sun, Lorenzo Carnevale, Marialuisa Perrotta, Zhe Ma, Benjamin Förstera, Karen Stanic, Chuankai Zhang, Xi Zhang, Piotr Szczepaniak, Mariaelvy Bianchini, Borhan R Saeed, Raimondo Carnevale, Desheng Hu, Ryszard Nosalski, Fabio Pallante, Michael BeerDonato Santovito, Ali Ertürk, Thomas C Mettenleiter, Barbara G Klupp, Remco T A Megens, Sabine Steffens, Jaroslav Pelisek, Hans-Henning Eckstein, Robert Kleemann, Livia Habenicht, Ziad Mallat, Jean-Baptiste Michel, Jürgen Bernhagen, Martin Dichgans, Giuseppe D'Agostino, Tomasz J Guzik, Peder S Olofsson, Changjun Yin, Christian Weber, Giuseppe Lembo, Daniela Carnevale, Andreas J R Habenicht

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.

Original languageEnglish
Pages (from-to)152-159
Number of pages8
JournalNature
Volume605
Issue number7908
Early online date27 Apr 2022
DOIs
Publication statusPublished - 5 May 2022

Keywords

  • Animals
  • Atherosclerosis/prevention & control
  • Disease Progression
  • EXPRESSION
  • Ganglia, Spinal
  • Ganglia, Sympathetic
  • HOST-DEFENSE
  • INFLAMMATION
  • LASER-CAPTURE MICRODISSECTION
  • MECHANISMS
  • Mice
  • NERVOUS-SYSTEM
  • Neurons/physiology
  • PAIN
  • PSEUDORABIES VIRUS
  • Plaque, Atherosclerotic/prevention & control
  • RECEPTOR
  • T-CELLS
  • HYPERTENSION

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