Table 1.

Microglial functions and relevance to sleep disorders.

Neuroinflammation	Experimental findings	Suggested implication
	Infection-induced sleep gain
Microglia are the main producers of cytokines in the central nervous system during inflammatory diseases.	IL-1 and TNFα are well-known to promote sleep in humans and in animal models (Krueger, 2008; Krueger et al., 2011; Zielinski et al., 2013; Krueger and Opp, 2016).	Pro-inflammatory cytokines may exert somnogenic effects by promoting microglial attraction to synapses (Karrer et al., 2015). TNFα induces the production of chemokines (CCL2, CCL7, and CXCL10) by neurons, which bind to corresponding receptors expressed by microglia and are known to promote microglial process extension (Karrer et al., 2015).
	Recreational-drug induced sleep loss
	PET scans of chronic d-METH self-administrating individuals reveals increased binding of the radiotracer [11C](R)-PK11195 that labels “activated” microglia (McCoy et al., 2007).
	In mice undergoing microglial depletion, the duration of daily wakefulness produced by d-METH is reduced by nearly 1 h. Ex vivo nitric oxide synthase (NOS) activity, and in vivo NOS expression are also elevated in cortical CD11b+ microglia from wild-type mice upon acute d-METH exposure. Additionally, CD11b+ cells are the only ones found to exhibit changes in sleep-regulatory IL-1β expression in response to d-METH (Wang et al., 2014).	The effects of d-METH on sleep and wakefulness could be mediated partly by microglia, through exacerbated oxidative stress and pro-inflammatory cytokine release (Wang et al., 2014).
	Narcolepsy
	Increased levels of IL-6 and TNFα are measured in the sera or plasma from narcoleptic patients (Cartier et al., 2005; Eltayeb et al., 2007; Dauvilliers et al., 2014).	Decrease in CCR expression could lead to a defect in the recognition and phagocytosis of damaged cells by microglia and consequently to a delayed resolution of acute inflammation. These defects could lead to enhanced autoimmunity resulting in the loss of hypocretin neurons.
	Reduced levels of microglia/macrophage-derived CCR1 and CCR3 are measured in peripheral blood samples from narcolepsy patients (Mignot et al., 1995; Tafti et al., 1996; Partinen et al., 2014).
Antigen presentation
Microglia can present antigens to T cells upon their binding to MHC class II expressed on their surface.	An increased microglial expression of MHC class II is measured in the central nervous system of narcoleptic dogs (Tafti, 2009).	Local infusion of a low-dose of the endotoxin lipopolysaccharide in rats, as a model of chronic inflammation, induces the loss of hypocretin neurons and increases the number of MHC class II-positive microglia in the lateral hypothalamus. Microglia-mediated inflammation might be a trigger for the loss of hypocretin neurons during narcolepsy (Maurovich-Horvat et al., 2014).
Phagocytosis
Microglia prune synapses in a complement-dependent manner in contexts of health and disease.	A distinctive complotype, i.e., a combination of polymorphisms defining complement activity: BfS, C4A3, and C4B1, was identified in narcopleptic patients (Savill et al., 2002).	Exacerbation of complement-dependent microglial phagocytic activity is a plausible mechanism leading to the loss of hypocretin neurons.
	Obstructive sleep apnea
	Sleep fragmentation
	Microglial co-localization with the marker of glutamatergic axon terminals VGLUT1 is increased after 5 days of chronic sleep deprivation in mouse prefrontal cortex (Bellesi et al., 2017). In parallel, the total length of microglial process arborization, and the proportion of the microglial population showing less ramified morphologies, are significantly reduced (Bellesi et al., 2017).	These observations suggest an exacerbated microglial pruning of synapes, which could be mediated by the classical complement pathway considering that expression of the complement protein C3 was concomitantly increased by sleep deprivation (Bellesi et al., 2017).
Immune surveillance	Chronic intermittent hypoxia
Microglia detect changes in homeostasis through their recognition of exogenous or endogenous danger signals, such as danger-associated molecular patterns (DAMPs).	Elevated levels of DAMPs are measured in blood samples from obstructive sleep apnea patients (Sapin et al., 2015), as well as in the hippocampus of rodent models of chronic intermittent hypoxia (Kiernan et al., 2016).	Microglia could respond to DAMPs induced by enhanced neuronal activity or psychological stress. The consequences on neuronal health and cognitive function are still undetermined however.