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 Beer, Donato 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 and Andreas J. R. Habenicht ()
Additional contact information
Sarajo K. Mohanta: Ludwig-Maximilians-Universität München (LMU)
Li Peng: Guizhou University of Traditional Chinese Medicine
Yuanfang Li: Ludwig-Maximilians-Universität München (LMU)
Shu Lu: Ludwig-Maximilians-Universität München (LMU)
Ting Sun: Ludwig-Maximilians-Universität München (LMU)
Lorenzo Carnevale: IRCCS Neuromed
Marialuisa Perrotta: IRCCS Neuromed
Zhe Ma: Ludwig-Maximilians-Universität München (LMU)
Benjamin Förstera: Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU)
Karen Stanic: Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU)
Chuankai Zhang: Ludwig-Maximilians-Universität München (LMU)
Xi Zhang: Ludwig-Maximilians-Universität München (LMU)
Piotr Szczepaniak: Jagiellonian University Collegium Medicum
Mariaelvy Bianchini: Ludwig-Maximilians-Universität München (LMU)
Borhan R. Saeed: University of Gothenburg
Raimondo Carnevale: IRCCS Neuromed
Desheng Hu: Deutsches Forschungszentrum für Gesundheit und Umwelt
Ryszard Nosalski: University of Glasgow
Fabio Pallante: IRCCS Neuromed
Michael Beer: University of Jena, Jena University Hospital
Donato Santovito: Ludwig-Maximilians-Universität München (LMU)
Ali Ertürk: Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU)
Thomas C. Mettenleiter: Friedrich-Loeffler-Institut
Barbara G. Klupp: Friedrich-Loeffler-Institut
Remco T. A. Megens: Ludwig-Maximilians-Universität München (LMU)
Sabine Steffens: Ludwig-Maximilians-Universität München (LMU)
Jaroslav Pelisek: Technical University of Munich
Hans-Henning Eckstein: Technical University of Munich
Robert Kleemann: The Netherlands Organization for Applied Scientific Research (TNO)
Livia Habenicht: Technische Universität München, Klinikum rechts der Isar
Ziad Mallat: University of Cambridge
Jean-Baptiste Michel: INSERM UMRS 1148, University Paris Diderot (P7), GH Bichat-Claude Bernard
Jürgen Bernhagen: German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance
Martin Dichgans: Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU)
Giuseppe D’Agostino: University of Manchester
Tomasz J. Guzik: Jagiellonian University Collegium Medicum
Peder S. Olofsson: Karolinska University Hospital
Changjun Yin: Ludwig-Maximilians-Universität München (LMU)
Christian Weber: Ludwig-Maximilians-Universität München (LMU)
Giuseppe Lembo: IRCCS Neuromed
Daniela Carnevale: IRCCS Neuromed
Andreas J. R. Habenicht: Ludwig-Maximilians-Universität München (LMU)

Nature, 2022, vol. 605, issue 7908, 152-159

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04673-6

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