Antimicrobial peptides signal need for sleep from peripheral wounds to the nervous system

Abstract

<jats:title>Abstract</jats:title><jats:p>Wounding triggers a protective innate immune response that includes the production of antimicrobial peptides and increased sleep. Little is known, however, about how peripheral wounds signal need for sleep to the nervous system. We found that during <jats:italic>C. elegans</jats:italic> larval molting, a tolloid/BMP-1-like protein promotes sleep through an epidermal innate immune pathway and the expression of more than a dozen antimicrobial peptide (AMP) genes. In the adult, epidermal injury activates innate immunity and turns up AMP production to trigger sleep. We show for one AMP, NLP-29, that it acts through the neuropeptide receptor NPR-12 in neurons that depolarize the sleep-active RIS neuron to induce sleep. Sleep in turn increases the chance of surviving injury. Thus, we found a novel mechanism by which peripheral wounds signal to the nervous system to increase protective sleep. Such a long-range somnogen signaling function of AMPs might also boost sleep in other animals including humans.</jats:p><jats:sec><jats:title>Highlights</jats:title><jats:list list-type="simple"><jats:list-item><jats:p>- Gain-of-function mutation in the tolloid/BMP-1-like NAS-38 protein increases sleep</jats:p></jats:list-item><jats:list-item><jats:p>- NAS-38 activates innate immunity pathways to ramp up STAT-dependent antimicrobial peptide (AMP) expression</jats:p></jats:list-item><jats:list-item><jats:p>- Wounding increases sleep through the innate immune response and AMPs</jats:p></jats:list-item><jats:list-item><jats:p>- Antimicrobial peptides are long-range somnogens that act through neuronal neuropeptide receptors to depolarize a sleep-active neuron</jats:p></jats:list-item><jats:list-item><jats:p>- Sleep increases the chance to survive injury</jats:p></jats:list-item></jats:list></jats:sec><jats:sec><jats:title>Graphical Abstract</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="183806v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec>

A sleep-active neuron can promote survival while sleep behavior is disturbed

“…RIS impairment has been shown to blunt survival during larval arrest and wounding [10, 11, 31]. We thus investigated how RIS depolarization levels affect survival in arrested first-stage larval worms.…”

“…Optogenetic manipulations showed that acute depolarization of RIS inhibits wakefulness activity such as feeding and locomotion [16,19], whereas hyperpolarization inhibits sleep and shortens survival [10,[20][21][22]. RIS is required for sleep during various stages and conditions [10,11,16,17,19,[23][24][25][26][27]. Larval starvation increases RIS activity and RIS is essential for starvation survival as it counteracts aging phenotype progression [10].…”

“…Central to the induction of sleep in all species are so-called sleep-active neurons that depolarize to inhibit wakefulness behavioral circuits and thus cause sleep [8, 9]. Sleep-active neurons are also important for survival, for example during starvation or after wounding [10, 11]. Little is known about how sleep-active neurons promote survival.…”

Dietary fiber ameliorates sleep disturbance connected to the gut–brain axis

“…47 Interestingly, host phagocytes such as macrophages and neutrophils can also digest peptidoglycan from the outer layers of intestinal flora to produce cell wall peptides (small glycopeptides), which are biologically active, some of which cause sleep responses. 48 The brain–gut peptide (BGP) is a small peptide with dual functions of hormone and neurotransmitter, present in both the central nervous system and the gastrointestinal tract and regulates the activities of the brain–gut system. Gastrin (GAS), somatostatin (SS) and melatonin (MT) all belong to the BGP, exert a protective effect on the gastrointestinal mucosa and play an important role in sleep.…”