Brain-specific interleukin-1 receptor accessory protein in sleep regulation

Interleukin (IL)-1β is involved in several brain functions, including sleep regulation. It promotes non-rapid eye movement (NREM) sleep via the IL-1 type I receptor. IL-1β/IL-1 receptor complex signaling requires adaptor proteins, e.g., the IL-1 receptor brain-specific accessory protein (AcPb). We have cloned and characterized rat AcPb, which shares substantial homologies with mouse AcPb and, compared with AcP, is preferentially expressed in the brain. Furthermore, rat somatosensory cortex AcPb mRNA varied across the day with sleep propensity, increased after sleep deprivation, and was induced by somnogenic doses of IL-1β. Duration of NREM sleep was slightly shorter and duration of REM sleep was slightly longer in AcPb knockout than wild-type mice. In response to lipopolysaccharide, which is used to induce IL-1β, sleep responses were exaggerated in AcPb knockout mice, suggesting that, in normal mice, inflammation-mediated sleep responses are attenuated by AcPb. We conclude that AcPb has a role in sleep responses to inflammatory stimuli and, possibly, in physiological sleep regulation.

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An interleukin-1 receptor fragment inhibits spontaneous sleep and muramyl dipeptide-induced sleep in rabbits

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.271.1.r101 ◽

1996 ◽

Vol 271 (1) ◽

pp. R101-R108 ◽

Cited By ~ 8

Author(s):

S. Takahashi ◽

L. Kapas ◽

J. Fang ◽

J. M. Seyer ◽

Y. Wang ◽

...

Keyword(s):

Bacterial Infections ◽

Interleukin 1 ◽

Muramyl Dipeptide ◽

Type I ◽

Amino Acid Residues ◽

Central Administration ◽

Sleep Regulation ◽

Systemic Injection ◽

Normal Sleep ◽

Receptor Fragment

Interleukin-1 (IL-1) is hypothesized to be involved in physiological sleep regulation and in sleep responses occurring during infectious disease. If this hypothesis is correct, then inhibition of endogenous IL-1 should reduce both normal sleep and N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)-induced sleep. MDP is a somnogenic substance derived from bacterial cell walls. We report here the effects of a synthetic IL-1 receptor fragment corresponding to amino acid residues 86-95 of the human type I IL-1 receptor (IL-1RF) on spontaneous sleep and IL-1 beta- and MDP-induced sleep and fever in rabbits. Two doses of the IL-1RF (25 and 50 micrograms) were injected into normal rabbits intracerebroventricularly (icv). Both doses significantly decreased spontaneous non-rapid eye movement sleep (NREMS) across a 22-h recording period. Pretreatment of rabbits with 25 micrograms of IL-1RF blocked the somnogenic actions of 10 ng icv IL-1. Similarly, central pretreatment of animals with 25 micrograms IL-1RF significantly attenuated the NREMS-promoting and REMS-suppressive actions of 150 pmol MDP injected centrally. The increase in NREMS and decrease in REMS induced by systemic injection of 12.5 micrograms/kg MDP were also significantly suppressed by central administration of 50 micrograms IL-1RF. In contrast, the febrile response induced by either intracerebroventricularly or intravenously injected MDP were not significantly affected by IL-1RF. These results support the hypothesis that endogenous, brain-derived IL-1 contributes to the maintenance of normal sleep and may mediate sleep responses to systemic as well as central bacterial infections.

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Abstract 13614: Nck1 Regulates Endothelial Activation and Blood Brain Integrity After Ischemia Reperfusion Injury

Circulation ◽

10.1161/circ.142.suppl_3.13614 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Mabruka Alfaidi ◽

Anthony W Orr

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Interleukin 1 ◽

Adaptor Proteins ◽

Neurological Deficits ◽

Type I ◽

Blood Brain

Introduction: Stroke remains a leading cause of disease disability worldwide. Rapid restoration of blood flow after occlusion is required to minimize brain damage. However, with the reperfusion there is upregulation to oxidative stress pathways that stimulates interleukin-1 activates kinase type I (IRAK-1) within endothelial cells leading to proinflammatory genes expression (ICAM-1/VCAM-1). We previously showed that the Nck family of adaptor proteins promotes oxidative stress-induced inflammation following ischemia reperfusion (IRI). Nck1 and Nck2 are two highly similar proteins but have inherent functional differences. Hypothesis: We hypothesized that Nck1 is required for IRAK-1 activation in response to IRI. Methods: Human brain endothelial cells (ECs) were genetically silenced for Nck1, Nck2, or interleukin-1 receptor type I kinase-1 (IRAK-1) and exposed to hydrogen peroxide (exogenous oxidative stress) or hypoxia re-oxygenation (endogenous oxidative stress). Additionally, adult male mice were subjected to 1 hour of middle cerebral artery occlusion (MCAO) followed by 24h reperfusion. Neurological deficits were assessed using the 24 sensorimotor scoring system. Infarct volume, blood brain barrier (BBB) integrity, and brain inflammatory profiles were assessed using immunostaining and immunoblotting. Results: Knock down of endothelial Nck1 or Nck2 of cells markedly reduced VCAM-1 and ICAM-1 expression and NF-κB activation in response to H 2 O 2 and hypoxia re-oxygenation. In ECs treated with the proinflammatory mediator interleukin-1 (IL-1β), there was upregulation of IRAK-1 and NF-κB activation. However, deletion of Nck1, but not Nck2, significantly decreased IRAK-1/ NF-κB activation by IL-1β. Moreover, Nck1 inhibition decreased endothelial permeability-induced by oxidative stress. In response to oxidative stress, Nck1 directly binds to IRAK-1. Nck1 KO mice had significantly less infarct volume and neurological deficits after MCAO/reperfusion. BBB disruption measured by Evans Blue extravasation and Fibrinogen staining was remarkably reduced in Nck1 KO mice. Conclusions: Nck1 promotes ischemia/reperfusion-induced inflammation, and brain injury, therefore, Nck1 inhibition is a promising therapy to improve IRI.

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An IL-1 receptor and an IL-1 receptor antagonist attenuate muramyl dipeptide- and IL-1-induced sleep and fever

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.4.r907 ◽

1993 ◽

Vol 265 (4) ◽

pp. R907-R913 ◽

Cited By ~ 8

Author(s):

L. Imeri ◽

M. R. Opp ◽

J. M. Krueger

Keyword(s):

Receptor Antagonist ◽

Eye Movement ◽

Brain Temperature ◽

Interleukin 1 ◽

Dose Range ◽

Muramyl Dipeptide ◽

Nrem Sleep ◽

Type I

It is hypothesized that the somnogenic and pyrogenic effects of muramyl dipeptide (MDP) are mediated via enhanced interleukin-1 (IL-1) production. To test this hypothesis the effects of intracerebroventricular (icv) administration of a recombinant human soluble type I IL-1 receptor (sIL-1r) and of the IL-1 receptor antagonist (IL-1ra) on MDP-induced sleep and fever were evaluated in rabbits. The sIL-1r recognized rabbit IL-1 beta, but it did not affect sleep or brain temperature across the dose range tested (1-50 micrograms) when injected icv into normal rabbits. Pretreatment of rabbits with 50 micrograms sIL-1r or 10 micrograms IL-1ra blocked human recombinant IL-1-enhanced nonrapid eye movement (NREM) sleep and fever. Thus both the sIL-1r and the IL-1ra were effective antagonists of IL-1 actions. When the animals were pretreated with either 50 micrograms sIL-1r or with 10 or 100 micrograms of the IL-1ra, the somnogenic effects of 150 pmol MDP were attenuated. However, the sIL-1r had little effect on MDP-induced febrile responses. These results suggest that the sIL-1r and the IL-1ra can function as antagonists of IL-1 actions in vivo and that MDP-induced sleep and fever are partially mediated by IL-1.

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Anti-interleukin-1 beta reduces sleep and sleep rebound after sleep deprivation in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.3.r688 ◽

1994 ◽

Vol 266 (3) ◽

pp. R688-R695 ◽

Cited By ~ 13

Author(s):

M. R. Opp ◽

J. M. Krueger

Keyword(s):

Sleep Deprivation ◽

Eye Movement ◽

Interleukin 1 ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Light Onset ◽

Deprivation Period ◽

Additional Support ◽

Physiological Sleep

Interleukin-1 (IL-1) is somnogenic and is hypothesized to be involved in physiological sleep regulation. Antibodies directed against rat IL-1 beta were used to further elucidate possible contributions of IL-1 to sleep regulation. Rabbit anti-rat IL-1 beta (anti-IL-1 beta) was injected intracerebroventricularly into normal rats 15 min before light onset. A 20-microgram dose of anti-IL-1 beta reduced non-rapid-eye-movement (NREM) sleep by 60 min during the subsequent 12-h slight period. There was no effect on rapid eye movement sleep after this dose of anti-IL-1 beta. The effects of anti-IL-1 beta on the enhancement of sleep after periods of sleep deprivation were also determined. When rats were deprived of sleep for 3-h beginning at light onset, the amount of time spent in NREM sleep increased for the remaining 9 h of the light period, regardless of whether control intracerebroventricular injections of pyrogen-free saline or rabbit immunoglobulin G were given during the deprivation period. However, when 20 micrograms anti-IL-1 beta were injected intracerebroventricularly during the sleep deprivation period, the expected NREM sleep rebound was completely blocked. Collectively, these data provide additional support for the hypothesis that IL-1 is involved in regulation of physiological sleep-wake activity.

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Selective role of Nck1 in atherogenic inflammation and plaque formation

10.1101/668129 ◽

2019 ◽

Cited By ~ 1

Author(s):

Mabruka Alfaidi ◽

Christina H. Acosta ◽

Dongdong Wang ◽

James G. Traylor ◽

A. Wayne Orr

Keyword(s):

Interleukin 1 ◽

Point Mutations ◽

Adaptor Proteins ◽

Endothelial Activation ◽

Sh2 Domain ◽

Type I ◽

Disturbed Flow

AbstractWhile CANTOS established the role of treating inflammation in atherosclerosis, our understanding of endothelial activation at atherosclerosis-prone sites remains limited. Disturbed flow at atheroprone regions primes plaque inflammation by enhancing endothelial NF-κB signaling. Herein, we demonstrate a novel role for the Nck adaptor proteins in disturbed flow-induced endothelial activation. Although highly similar, only Nck1 deletion, but not Nck2 deletion, limits flow-induced NF-κB activation and proinflammatory gene expression. Nck1 knockout mice show reduced endothelial activation and inflammation in both models of disturbed flow and high fat diet-induced atherosclerosis. Bone marrow chimeras confirm that vascular Nck1, but not hematopoietic Nck1, mediates this effect. In contrast, endothelial Nck2 depletion does not affect endothelial activation or atherosclerosis. Domain swap experiments and point mutations identify the Nck1 SH2 domain and the first SH3 domain as critical for flow-induced endothelial activation. We further characterize Nck1’s proinflammatory role by identifying interleukin-1 type I receptor kinase-1 (IRAK-1) as a Nck1-selective binding partner, demonstrating IRAK-1 activation by disturbed flow requires Nck1 in vitro and in vivo, showing endothelial Nck1 and IRAK-1 staining in early human atherosclerosis, and demonstrating that disturbed flow-induced endothelial activation requires IRAK-1. Taken together, our data reveal a hitherto unknown link between Nck1 and IRAK-1 in atherogenic inflammation.

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