Role of sleep deprivation in immune-related disease risk and outcomes

Abstract

Modern societies are experiencing an increasing trend of reduced sleep duration, with nocturnal sleeping time below the recommended ranges for health. Epidemiological and laboratory studies have demonstrated detrimental effects of sleep deprivation on health. Sleep exerts an immune-supportive function, promoting host defense against infection and inflammatory insults. Sleep deprivation has been associated with alterations of innate and adaptive immune parameters, leading to a chronic inflammatory state and an increased risk for infectious/inflammatory pathologies, including cardiometabolic, neoplastic, autoimmune and neurodegenerative diseases. Here, we review recent advancements on the immune responses to sleep deprivation as evidenced by experimental and epidemiological studies, the pathophysiology, and the role for the sleep deprivation-induced immune changes in increasing the risk for chronic diseases. Gaps in knowledge and methodological pitfalls still remain. Further understanding of the causal relationship between sleep deprivation and immune deregulation would help to identify individuals at risk for disease and to prevent adverse health outcomes.

Fig. 1. Brain cytokines (CYT, orange circles) network and different suggested routes by which peripherally released inflammatory signals can bypass the blood–brain barrier and circumventricular organs (CVOs), and activate the central nervous system: humoral, cellular, and neural pathways.

CCL-2: C-C motif chemokine ligand-2; CXCL-10: C-X-C motif chemokine ligand 10; IL-1: interleukin-1; mNTS: medial nucleus tractus solitarius; PGE₂: prostaglandin E2; TNF-α: tumor necrosis factor-α.

Fig. 2. Immune consequences of sleep deprivation.

Sleep deprivation, as induced experimentally or in the context of habitual short sleep, has been found to be associated with alterations in the circulating numbers and/or activity of total leukocytes and specific cell subsets, elevation of systemic and tissue (e.g., brain) pro-inflammatory markers including cytokines (e.g., interleukins [IL], tumor necrosis factor [TNF]-α), chemokines and acute phase proteins (such as C reactive Protein [CRP]), altered antigen presentation (reduced dendritic cells, altered pattern of activating cytokines, etc.), lowered Th1 response, higher Th2 response, and reduced antibody production. Furthermore, altered monocytes responsiveness to immunological challenges such as lipopolysaccharide (LPS) may contribute to sleep deprivation-associated immune modulation. Hypothesized links between immune dysregulation by sleep deprivation and the risk for immune-related diseases, such as infectious, cardiovascular, metabolic, and neurodegenerative and neoplastic diseases, are shown. The illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License. APC: antigen-presenting cells.

Fig. 3. Pro-inflammatory molecular pathways induced by sleep deprivation.

A schematic model of potential mechanistic pathways linking sleep deprivation and inflammatory immune activation is depicted. Sleep deprivation is associated with activation of the sympathetic nervous system and release of norepinephrine and epinephrine into the systemic circulation, as well as to some extent with impaired hypothalamus-pituitary axis stimulation. These neuromediators may act along with other potential stimuli accumulated following sleep deprivation including reactive oxygen species (ROS), adenosine, metabolic waste products (e.g., β-amyloid) not cleared during normal sleep, gut microbiota dysbiosis leading to altered local and systemic pattern of metabolic products, as well as with changes in the profile of neuro-endocrine hormones, such as prolactin, growth hormone, and altered circadian rhythm of melatonin secretion. In immune cells located in the brain and the peripheral tissues, these stimuli may in concert trigger inflammatory activation, with release of cytokines, chemokines, acute phase protein, etc. via the recruitment of transcriptional regulators of pro-inflammatory gene expression, mainly nuclear factor (NF)-κB, and disturbing the circadian rhythmicity of gene expression of both clock genes and metabolic, immune and stress response genes (see text for further detail). E: epinephrine; NE: norepinephrine; TLR: Toll-like receptor. Arrows indicate stimulation; lines indicate inhibition. The illustrations were modified from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Common Attribution 3.0 Generic License.