Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease

Karin A. Ziegler; Andrea Ahles; Anne Dueck; Dena Esfandyari; Pauline Pichler; Karolin Weber; Stefan Kotschi; Alexander Bartelt; Inga Sinicina; Matthias Graw; Heinrich Leonhardt; Ludwig T. Weckbach; Steffen Massberg; Martina Schifferer; Mikael Simons; Luciano Hoeher; Jie Luo; Ali Ertürk; Gabriele G. Schiattarella; Yassine Sassi; Thomas Misgeld; Stefan Engelhardt

doi:10.1126/science.abn6366

Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease

Karin A. Ziegler, Andrea Ahles, Anne Dueck, Dena Esfandyari, Pauline Pichler, Karolin Weber, Stefan Kotschi, Alexander Bartelt, Inga Sinicina, Matthias Graw, Heinrich Leonhardt, Ludwig T. Weckbach, Steffen Massberg, Martina Schifferer, Mikael Simons, Luciano Hoeher, Jie Luo, Ali Ertürk, Gabriele G. Schiattarella, Yassine SassiThomas Misgeld, Stefan Engelhardt

Lehrstuhl für Pharmakologie und Toxikologie

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

28 Zitate (Scopus)

Abstract

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

Originalsprache	Englisch
Seiten (von - bis)	285-290
Seitenumfang	6
Fachzeitschrift	Science
Jahrgang	381
Ausgabenummer	6655
DOIs	https://doi.org/10.1126/science.abn6366
Publikationsstatus	Veröffentlicht - 21 Juli 2023

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10.1126/science.abn6366

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Ziegler, K. A., Ahles, A., Dueck, A., Esfandyari, D., Pichler, P., Weber, K., Kotschi, S., Bartelt, A., Sinicina, I., Graw, M., Leonhardt, H., Weckbach, L. T., Massberg, S., Schifferer, M., Simons, M., Hoeher, L., Luo, J., Ertürk, A., Schiattarella, G. G., ... Engelhardt, S. (2023). Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease. Science, 381(6655), 285-290. https://doi.org/10.1126/science.abn6366

@article{4d92d26bb654477e9c9e1122e309082c,

title = "Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease",

abstract = "Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.",

author = "Ziegler, {Karin A.} and Andrea Ahles and Anne Dueck and Dena Esfandyari and Pauline Pichler and Karolin Weber and Stefan Kotschi and Alexander Bartelt and Inga Sinicina and Matthias Graw and Heinrich Leonhardt and Weckbach, {Ludwig T.} and Steffen Massberg and Martina Schifferer and Mikael Simons and Luciano Hoeher and Jie Luo and Ali Ert{\"u}rk and Schiattarella, {Gabriele G.} and Yassine Sassi and Thomas Misgeld and Stefan Engelhardt",

year = "2023",

month = jul,

day = "21",

doi = "10.1126/science.abn6366",

language = "English",

volume = "381",

pages = "285--290",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6655",

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Ziegler, KA, Ahles, A, Dueck, A, Esfandyari, D, Pichler, P, Weber, K, Kotschi, S, Bartelt, A, Sinicina, I, Graw, M, Leonhardt, H, Weckbach, LT, Massberg, S, Schifferer, M, Simons, M, Hoeher, L, Luo, J, Ertürk, A, Schiattarella, GG, Sassi, Y, Misgeld, T & Engelhardt, S 2023, 'Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease', Science, Jg. 381, Nr. 6655, S. 285-290. https://doi.org/10.1126/science.abn6366

TY - JOUR

T1 - Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease

AU - Ziegler, Karin A.

AU - Ahles, Andrea

AU - Dueck, Anne

AU - Esfandyari, Dena

AU - Pichler, Pauline

AU - Weber, Karolin

AU - Kotschi, Stefan

AU - Bartelt, Alexander

AU - Sinicina, Inga

AU - Graw, Matthias

AU - Leonhardt, Heinrich

AU - Weckbach, Ludwig T.

AU - Massberg, Steffen

AU - Schifferer, Martina

AU - Simons, Mikael

AU - Hoeher, Luciano

AU - Luo, Jie

AU - Ertürk, Ali

AU - Schiattarella, Gabriele G.

AU - Sassi, Yassine

AU - Misgeld, Thomas

AU - Engelhardt, Stefan

PY - 2023/7/21

Y1 - 2023/7/21

N2 - Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

AB - Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

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SN - 0036-8075

VL - 381

SP - 285

EP - 290

JO - Science

JF - Science

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ER -

Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease

Abstract

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