TY - JOUR
T1 - Neuroimmune cardiovascular interfaces control atherosclerosis
AU - Mohanta, Sarajo K
AU - Peng, Li
AU - Li, Yuanfang
AU - Lu, Shu
AU - Sun, Ting
AU - Carnevale, Lorenzo
AU - Perrotta, Marialuisa
AU - Ma, Zhe
AU - Förstera, Benjamin
AU - Stanic, Karen
AU - Zhang, Chuankai
AU - Zhang, Xi
AU - Szczepaniak, Piotr
AU - Bianchini, Mariaelvy
AU - Saeed, Borhan R
AU - Carnevale, Raimondo
AU - Hu, Desheng
AU - Nosalski, Ryszard
AU - Pallante, Fabio
AU - Beer, Michael
AU - Santovito, Donato
AU - Ertürk, Ali
AU - Mettenleiter, Thomas C
AU - Klupp, Barbara G
AU - Megens, Remco T A
AU - Steffens, Sabine
AU - Pelisek, Jaroslav
AU - Eckstein, Hans-Henning
AU - Kleemann, Robert
AU - Habenicht, Livia
AU - Mallat, Ziad
AU - Michel, Jean-Baptiste
AU - Bernhagen, Jürgen
AU - Dichgans, Martin
AU - D'Agostino, Giuseppe
AU - Guzik, Tomasz J
AU - Olofsson, Peder S
AU - Yin, Changjun
AU - Weber, Christian
AU - Lembo, Giuseppe
AU - Carnevale, Daniela
AU - Habenicht, Andreas J R
N1 - © 2022. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5/5
Y1 - 2022/5/5
N2 - 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.
AB - 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.
KW - Animals
KW - Atherosclerosis/prevention & control
KW - Disease Progression
KW - EXPRESSION
KW - Ganglia, Spinal
KW - Ganglia, Sympathetic
KW - HOST-DEFENSE
KW - INFLAMMATION
KW - LASER-CAPTURE MICRODISSECTION
KW - MECHANISMS
KW - Mice
KW - NERVOUS-SYSTEM
KW - Neurons/physiology
KW - PAIN
KW - PSEUDORABIES VIRUS
KW - Plaque, Atherosclerotic/prevention & control
KW - RECEPTOR
KW - T-CELLS
KW - HYPERTENSION
U2 - 10.1038/s41586-022-04673-6
DO - 10.1038/s41586-022-04673-6
M3 - Article
C2 - 35477759
SN - 0028-0836
VL - 605
SP - 152
EP - 159
JO - Nature
JF - Nature
IS - 7908
ER -