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

• 成果类型: Article
• 署名作者: Ziegler, Karin A.; Ahles, Andrea; Dueck, Anne; Esfandyari, Dena; Pichler, Pauline; Weber, Karolin; Kotschi, Stefan; Bartelt, Alexander; Sinicina, Inga; Graw, Matthias; Leonhardt, Heinrich; Weckbach, Ludwig T.; Massberg, Steffen; Schifferer, Martina; Simons, Mikael; Hoeher, Luciano; Luo, Jie; Ertuerk, Ali; Schiattarella, Gabriele G.; Sassi, Yassine; Misgeld, Thomas; Engelhardt, Stefan
• 署名单位: Technical University of Munich; Munich Heart Alliance; German Centre for Cardiovascular Research; University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Harvard University; Harvard T.H. Chan School of Public Health; University of Munich; University of Munich; University of Munich; University of Munich; Helmholtz Association; German Center for Neurodegenerative Diseases (DZNE); University of Munich; Technical University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Munich; German Centre for Cardiovascular Research; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8218
• DOI: 10.1126/science.abn6366
• 发表日期: 2023-07-21
• 页码: 285-290
• 关键词: superior cervical-ganglion; expression; transgene; melatonin; neurons; atrial

摘要

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.