Inflammation-sleep interface in brain disease: TNF, insulin, orexin

Abstract

The depth, pattern, timing and duration of unconsciousness, including sleep, vary greatly in inflammatory disease, and are regarded as reliable indicators of disease severity. Similarly, these indicators are applicable to the encephalopathies of sepsis, malaria, and trypanosomiasis, and to viral diseases such as influenza and AIDS. They are also applicable to sterile neuroinflammatory states, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, stroke and type-2 diabetes, as well as in iatrogenic brain states following brain irradiation and chemotherapy. Here we make the case that the cycles of unconsciousness that constitute normal sleep, as well as its aberrations, which range from sickness behavior through daytime sleepiness to the coma of inflammatory disease states, have common origins that involve increased inflammatory cytokines and consequent insulin resistance and loss of appetite due to reduction in orexigenic activity. Orexin reduction has broad implications, which are as yet little appreciated in the chronic inflammatory conditions listed, whether they be infectious or sterile in origin. Not only is reduction in orexin levels characterized by loss of appetite, it is associated with inappropriate and excessive sleep and, when dramatic and chronic, leads to coma. Moreover, such reduction is associated with impaired cognition and a reduction in motor control. We propose that advanced understanding and appreciation of the importance of orexin as a key regulator of pathways involved in the maintenance of normal appetite, sleep patterns, cognition, and motor control may afford novel treatment opportunities.

Sepsis and the orexin system

“…Indeed, i.c.v. OXA improved arousal, temperature, and heart and respiratory rates when OXergic activity was significantly reduced to one-sixth of baseline in a septic state induced by cecal ligation and puncture [34]. However, as there has only been this one report to suggest that i.c.v.…”

“…In inflammatory brain disease models, glucagon-like peptide-1 (GLP-1) mimetics have been reported to reverse memory impairment, synaptic and neuronal loss, and behavioral dysfunction [34]. As GLP-1 mimetics have been reported to activate OXergic neurons in ex vivo hypothalamic slices, GLP-1 mimetics could be functional OX receptor agonists.…”

“…In addition, cytotoxic chemotherapy produced hypothalamic inflammation and suppressed hypothalamic OXergic activity, and this fatigue was reversed by i.c.v. OXA [34]. Thus, the pathophysiologic symptoms of sepsis might be improved by an increase in OXergic activity.…”

iRhoms in the brain – a new frontier?

“…6 Interestingly, inflammation and the iRhom2/ADAM17 substrate TNFa are also known to affect sleep in mice and humans, so the iRhoms could be involved in controlling different aspects of this restorative and protective process. 7 Overall, the serendipitous discovery of the differential regulation of ADAM17 by iRhoms1 and 2 in the brain promises to open up a new frontier for exploration of the function of these molecules. The evolutionarily conserved role of the EGFR and its ligands in sleep and regulating locomotor activity raises questions about the role of iRhom1/ADAM17-dependent shedding of TGFa in this process.…”

“…Stefan F Lichtenthaler 1,2,3,4 , Bruce F O'Hara 5 , and Carl P Blobel 4,6,7 The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) orchestrates cell-cell interactions and has a key role in inflammation, development and in diseases such as Rheumatoid Arthritis and Cancer. ADAM17 is responsible for liberating the pro-inflammatory cytokine TNFa and most EGFR-ligands from their membrane anchor, thereby keeping a close reign on the TNFa-and EGFR signaling pathways.…”