Where does inflammation in insomnia come from? and does it matter for comorbidity? Free

Among the various adaptive functions of normal sleep, the regulation of immune system historically received much attention in basic sleep science [1–5]. Inflammation can be defined as an evolutionary-based primary defense of the body against physical or psychosocial threats. Inflammation is therefore a normal and adaptive process as far as it is proportionate and directed to the appropriate target. Substantial abnormalities in the timing and strength of inflammatory response can instead cause acute or chronic illness [6]. Thus, a traditional contribution of sleep research to this field regarded how sleep could influence the trajectories from normal to pathological inflammatory response [5, 7]. Major findings in this context highlighted, for example, that sleep deprivation may induce chronobiological changes in proinflammatory markers secretion [8] and promote the activation of nuclear factor-kappaB, which is a key transcriptional control pathway in the inflammatory response [4].

More recently, several research groups attempted to translate basic knowledge about the sleep-immune pathways into the study of clinically relevant topics. These included the role of experimentally induced sleep loss and sleep disorders (i.e. insomnia) in the pathophysiology of inflammation-related diseases (e.g. [9–14], and mortality [15–17]), the interactions between inflammatory markers and pathological sleep conditions in influencing mental health [18–21], as well as the efficacy of sleep-promoting interventions, i.e. cognitive behavioral therapy for insomnia (CBT-I), in reducing inflammation [22–24].

The study of Zhang et al. [25], applied traditional pairwise meta-analytic techniques to investigate the presence of abnormal levels of inflammation in several disturbed sleep conditions, in combination with genetic variance analysis, i.e. Mendelian randomization, to disentangle the directionality of the association between inflammation and sleep. Authors followed standard recommendations for systematic reviews and meta-analyses [26] and used genome-wide association statistics from the UK Biobank, a population-based study including genetics and sleep information. Main results revealed that individuals with insomnia symptoms, but not those with excessive daytime sleepiness, exhibited higher peripheral levels of pro-inflammatory markers such as interleukin (IL)-6 and IL-1β, tumor necrosis factor-α, and C-reactive protein (CRP), compared to healthy controls in meta-analysis. However, results of the two sample Mendelian randomization, an analytic method using genetic variants as instrumental variables for modifiable risk factors, which is not susceptible to confounding and reverse causality bias, suggested no existence of causality between insomnia and inflammation, in either direction. This result echoed other recently published Mendelian randomization studies yielding no causal associations between insomnia and incidence of inflammatory illnesses such as inflammatory bowel diseases, i.e. ulcerative colitis and Crohn’s disease [27] and rheumatoid arthritis [28], although evidence in rheumatoid arthritis is more controversial, with other authors finding substantial impact of genetically determined insomnia on this illness [29].

Instead, the study of Zhang et al. [25] showed that inflammation appeared to be causally involved in extreme sleep durations, and particularly long sleep. The latter is consistent with the sickness behavior model of inflammation-induced shortened or prolonged sleep duration, according to which inflammation, and specifically cytokines (e.g. IL-6), may cause changes in sleep duration via peripheral-central pathways (e.g. [21, 30]).

Thus, if inflammation does not seem strongly predicted by the genetic variance associated with insomnia, as Zhang et al. [25] elegantly showed, one could ask where does inflammation in insomnia come from? Authors discussed these contradictory results invoking comorbidity. Insomnia is in fact highly comorbid in individuals with mental disorders and physical diseases in which inflammation may be a key component. Above all, insomnia is complained by up to 90% of individuals with depression [31], and up to 27% of individuals with depression [32] exhibited a state of low-grade chronic inflammation (i.e. a CRP levels above 3 mg/L). Longitudinal studies showed that CRP and IL-6 may be precursors and/or consequences of depression, and especially physical symptoms of depression [33]. Moreover, evidence from Mendelian randomization studies showed that inflammation may be causally involved in depression [34, 35]. So, it is possible that comorbid depression and abnormal sleep quantity may explain the elevated inflammation found in a subgroup of individuals with insomnia, which Carroll estimated at about 22% of total individuals with insomnia. Crucially, Zhang et al. were limited in separating samples with and without comorbidity due to insufficient data. Moreover, only 2 out of 10 studies included in Zhang et al. meta-analysis adopted objective sleep measures, and the Mendelian randomization analysis on sleep duration completely relied on self-reported habitual sleep duration; thus, the associations between genetically derived objective sleep duration and inflammation remain largely unknown.

Most importantly, evidence produced using Mendelian randomization lay at the interface between observational studies and randomized controlled trials, and should therefore, be cautiously interpreted in the context of existing evidence from other sources and using different research designs [36]. For instance, a recent well-conducted study employing a randomized crossover design showed that experimentally induced prolonged sleep dis-continuity, which could be considered an experimental model of insomnia, downregulated inflammatory resolution mediators such as D-series resolvins [37]. Thus, whether insomnia may be causally involved in inflammation (and vice versa) remains an open question. Finally, independent from its causes, higher inflammation in individuals with insomnia may increase the risk of developing and/or maintaining comorbidity and specially depression. In this direction, we recently showed that in older women, higher peripheral high-sensitivity CRP may mediate the association between nighttime insomnia symptoms and depression using three waves data from the English Longitudinal Study of Aging even after controlling for relevant confounders [19]; additionally, Piber et al. [38] showed that higher morning peripheral interferon-γ, a pro-inflammatory marker, may moderate the association between previous night disrupted sleep and daily depressive symptoms using an intense longitudinal assessment.

In conclusion, the study of Zhang et al. provided highly relevant insights on the associations between inflammation and disturbed sleep conditions, corroborating previous findings on increased adaptive immune activation in individuals with insomnia complaints. Nonetheless, further research is still needed to clearly disentangle the causality between inflammation and insomnia, as well as the role played by individual differences and comorbidity.

Disclosures Statement

Financial disclosure: The author has nothing to disclose. Nonfinancial disclosure: The author has nothing to disclose.

References