Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease 2023 Ziegler et al

Editor’s summary

Patients with heart disease frequently present with low melatonin levels and show disruptions in their sleep–wake cycles. Although disordered sleep adds considerably to the overall disease burden of these patients, the mechanisms that underlie this phenomenon remain unclear. Ziegler et al. report in both mice and humans that sleep disruption in cardiac disease is driven by the loss of neurons that normally project from the superior cervical ganglia into the pineal gland, which secretes melatonin (see the Perspective by Davis and Attwell). They found that heart disease triggers the infiltration of macrophages into superior cervical ganglia, where they orchestrate neuronal cell death. Depletion of macrophages or inhibition of their activation attenuated these defects in a mouse model of heart disease, suggesting an actionable target for future therapies. — Seth Thomas Scanlon

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.

Paywall, https://www.science.org/doi/10.1126/science.abn6366