Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner

Abstract

It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1β (IL-1β) may mediate this effect as it can affect glucoregulation, it is overexpressed in the ‘healthy’ brain during increased neuronal activity, and it supports high-energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL-1β-induced hypoglycemia. Here, we show that IL-1β adjusts glucoregulation by inducing its own production in the brain, and that IL-1β-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88)-dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1β stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1β effects on brain metabolism are most likely maintained by IL-1β auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity-dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1β to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1β production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Sims JE, Smith DE . The IL-1 family: regulators of immunity. Nat Rev Immunol 2010; 10: 89–102.

    Article  CAS  Google Scholar 

  2. Anisman H, Merali Z, Poulter MO, Hayley S . Cytokines as a precipitant of depressive illness: animal and human studies. Curr Pharm Des 2005; 11: 963–972.

    CAS  Google Scholar 

  3. Di Filippo M, Sarchielli P, Picconi B, Calabresi P . Neuroinflammation and synaptic plasticity: theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders. Trends Pharmacol Sci 2008; 29: 402–412.

    Article  CAS  Google Scholar 

  4. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

    Article  CAS  Google Scholar 

  5. Muller N, Ackenheil M . Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 1–33.

    Article  CAS  Google Scholar 

  6. Na KS, Jung HY, Kim YK . The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2014; 48: 277–286.

    Article  CAS  Google Scholar 

  7. Besedovsky H, del Rey A, Sorkin E, Dinarello CA . Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986; 233: 652–654.

    Article  CAS  Google Scholar 

  8. Besedovsky HO, del Rey A . Regulating inflammation by glucocorticoids. Nat Immunol 2006; 7: 537.

    Article  CAS  Google Scholar 

  9. Besedovsky HO, del Rey A . Central and peripheral cytokines mediate immune-brain connectivity. Neurochem Res 2011; 36: 1–6.

    Article  CAS  Google Scholar 

  10. Coogan AN, O'Neill LA, O'Connor JJ . The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro. Neuroscience 1999; 93: 57–69.

    Article  CAS  Google Scholar 

  11. Ross FM, Allan SM, Rothwell NJ, Verkhratsky A . A dual role for interleukin-1 in LTP in mouse hippocampal slices. J Neuroimmunol 2003; 144: 61–67.

    Article  CAS  Google Scholar 

  12. Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO . A neuromodulatory role of interleukin-1beta in the hippocampus. Proc Natl Acad Sci USA 1998; 95: 7778–7783.

    Article  CAS  Google Scholar 

  13. Spulber S, Mateos L, Oprica M, Cedazo-Minguez A, Bartfai T, Winblad B et al. Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain. J Neuroimmunol 2009; 208: 46–53.

    Article  CAS  Google Scholar 

  14. Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 2003; 13: 826–834.

    Article  CAS  Google Scholar 

  15. Ben Menachem-Zidon O, Avital A, Ben-Menahem Y, Goshen I, Kreisel T, Shmueli EM et al. Astrocytes support hippocampal-dependent memory and long-term potentiation via interleukin-1 signaling. Brain Behav Immun 2011; 25: 1008–1016.

    Article  CAS  Google Scholar 

  16. del Rey A, Balschun D, Wetzel W, Randolf A, Besedovsky HO . A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning. Brain Behav Immun 2013; 33: 15–23.

    Article  CAS  Google Scholar 

  17. Yirmiya R, Goshen I . Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011; 25: 181–213.

    Article  CAS  Google Scholar 

  18. Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, Wunderbaldinger G, Gassner M, Sandkuhler J . Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J Neurosci 2013; 33: 6540–6551.

    Article  CAS  Google Scholar 

  19. Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, Satoh M . Immobilization stress induces interleukin-1 beta mRNA in the rat hypothalamus. Neurosci Lett 1991; 123: 254–256.

    Article  CAS  Google Scholar 

  20. del Rey A, Yau HJ, Randolf A, Centeno MV, Wildmann J, Martina M et al. Chronic neuropathic pain-like behavior correlates with IL-1beta expression and disrupts cytokine interactions in the hippocampus. Pain 2011; 152: 2827–2835.

    Article  CAS  Google Scholar 

  21. Belanger M, Allaman I, Magistretti PJ . Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011; 14: 724–738.

    Article  CAS  Google Scholar 

  22. McNay EC, Fries TM, Gold PE . Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci USA 2000; 97: 2881–2885.

    Article  CAS  Google Scholar 

  23. Sadgrove MP, Beaver CJ, Turner DA . Effects of relative hypoglycemia on LTP and NADH imaging in rat hippocampal slices. Brain Res 2007; 1165: 30–39.

    Article  CAS  Google Scholar 

  24. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A . Insulin in the brain: sources, localization and functions. Mol Neurobiol 2013; 47: 145–171.

    Article  CAS  Google Scholar 

  25. Zhao W, Wu X, Xie H, Ke Y, Yung WH . Permissive role of insulin in the expression of long-term potentiation in the hippocampus of immature rats. Neurosignals 2010; 18: 236–245.

    Article  CAS  Google Scholar 

  26. Zhao WQ, Chen H, Quon MJ, Alkon DL . Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490: 71–81.

    Article  CAS  Google Scholar 

  27. Besedovsky HO, del Rey A . Physiologic Versus Diabetogenic Effects of Interleukin-1: a Question of Weight. Curr Pharm Des 2014; 20: 4733–4740.

    Article  CAS  Google Scholar 

  28. Vega C, Pellerin L, Dantzer R, Magistretti PJ . Long-term modulation of glucose utilization by IL-1 alpha and TNF-alpha in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms. Glia 2002; 39: 10–18.

    Article  Google Scholar 

  29. Wang J, Li G, Wang Z, Zhang X, Yao L, Wang F et al. High glucose-induced expression of inflammatory cytokines and reactive oxygen species in cultured astrocytes. Neuroscience 2012; 202: 58–68.

    Article  CAS  Google Scholar 

  30. Wang CH, Wang WT, Cheng SY, Hung WT, Wu TL, Hsueh CM . Leptin and interleukin-1beta modulate neuronal glutamate release and protect against glucose-oxygen-serum deprivation. Curr Neurovasc Res 2010; 7: 223–237.

    Article  CAS  Google Scholar 

  31. del Rey A, Roggero E, Randolf A, Mahuad C, McCann S, Rettori V et al. IL-1 resets glucose homeostasis at central levels. Proc Natl Acad Sci USA 2006; 103: 16039–16044.

    Article  CAS  Google Scholar 

  32. Besedovsky H, del Rey A . Neuroendocrine and metabolic responses induced by interleukin-1. J Neurosci Res 1987; 18: 172–178.

    Article  CAS  Google Scholar 

  33. Oguri S, Motegi K, Iwakura Y, Endo Y . Primary role of interleukin-1 alpha and interleukin-1 beta in lipopolysaccharide-induced hypoglycemia in mice. Clin Diagn Lab Immunol 2002; 9: 1307–1312.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Balschun D, Wetzel W, del Rey A, Pitossi F, Schneider H, Zuschratter W et al. Interleukin-6: a cytokine to forget. FASEB J 2004; 18: 1788–1790.

    Article  CAS  Google Scholar 

  35. del Rey A, Besedovsky H . Interleukin 1 affects glucose homeostasis. Am J Physiol 1987; 253: R794–R798.

    CAS  PubMed  Google Scholar 

  36. Endo Y . Parallel relationship between the increase in serotonin in the liver and the hypoglycaemia induced in mice by interleukin-1 and tumour necrosis factor. Immunol Lett 1991; 27: 75–79.

    Article  CAS  Google Scholar 

  37. Ota K, Wildmann J, Ota T, Besedovsky HO, del Rey A . Interleukin-1beta and insulin elicit different neuroendocrine responses to hypoglycemia. Ann NY Acad Sci 2009; 1153: 82–88.

    Article  CAS  Google Scholar 

  38. Rothwell NJ, Luheshi GN . Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2000; 23: 618–625.

    Article  CAS  Google Scholar 

  39. Ye K, Koch KC, Clark BD, Dinarello CA . Interleukin-1 down-regulates gene and surface expression of interleukin-1 receptor type I by destabilizing its mRNA whereas interleukin-2 increases its expression. Immunology 1992; 75: 427–434.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998; 9: 143–150.

    Article  CAS  Google Scholar 

  41. Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A et al. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci USA 1998; 95: 10402–10406.

    Article  CAS  Google Scholar 

  42. Depino AM, Alonso M, Ferrari C, del Rey A, Anthony D, Besedovsky H et al. Learning modulation by endogenous hippocampal IL-1: blockade of endogenous IL-1 facilitates memory formation. Hippocampus 2004; 14: 526–535.

    Article  CAS  Google Scholar 

  43. Hernangomez M, Mestre L, Correa FG, Loria F, Mecha M, Inigo PM et al. CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation. Glia 2012; 60: 1437–1450.

    Article  Google Scholar 

  44. Pitossi F, del Rey A, Kabiersch A, Besedovsky H . Induction of cytokine transcripts in the central nervous system and pituitary following peripheral administration of endotoxin to mice. J Neurosci Res 1997; 48: 287–298.

    Article  CAS  Google Scholar 

  45. Ghezzi P, Dinarello CA . IL-1 induces IL-1. III. Specific inhibition of IL-1 production by IFN-gamma. J Immunol 1988; 140: 4238–4244.

    CAS  PubMed  Google Scholar 

  46. Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 2001; 4: 507–512.

    Article  CAS  Google Scholar 

  47. Bittsansky M, Vybohova D, Dobrota D . Proton magnetic resonance spectroscopy and its diagnostically important metabolites in the brain. Gen Physiol Biophys 2012; 31: 101–112.

    Article  CAS  Google Scholar 

  48. Schwarcz A, Natt O, Watanabe T, Boretius S, Frahm J, Michaelis T . Localized proton MRS of cerebral metabolite profiles in different mouse strains. Magn Reson Med 2003; 49: 822–827.

    Article  CAS  Google Scholar 

  49. Wyss M, Kaddurah-Daouk R . Creatine and creatinine metabolism. Physiol Rev 2000; 80: 1107–1213.

    Article  CAS  Google Scholar 

  50. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM . N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007; 81: 89–131.

    Article  CAS  Google Scholar 

  51. Soares DP, Law M . Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications. Clin Radiol 2009; 64: 12–21.

    Article  CAS  Google Scholar 

  52. Hosoi T, Yokoyama S, Matsuo S, Akira S, Ozawa K . Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS One 2010; 5: e12537.

    Article  Google Scholar 

  53. Drouin-Ouellet J, LeBel M, Filali M, Cicchetti F . MyD88 deficiency results in both cognitive and motor impairments in mice. Brain Behav Immun 2012; 26: 880–885.

    Article  CAS  Google Scholar 

  54. Klapproth J, Castell J, Geiger T, Andus T, Heinrich PC . Fate and biological action of human recombinant interleukin 1 beta in the rat in vivo. Eur J Immunol 1989; 19: 1485–1490.

    Article  CAS  Google Scholar 

  55. Hao W, Liu Y, Liu S, Walter S, Grimm MO, Kiliaan AJ et al. Myeloid differentiation factor 88-deficient bone marrow cells improve Alzheimer's disease-related symptoms and pathology. Brain 2011; 134: 278–292.

    Article  Google Scholar 

  56. Kang J, Rivest S . MyD88-deficient bone marrow cells accelerate onset and reduce survival in a mouse model of amyotrophic lateral sclerosis. J Cell Biol 2007; 179: 1219–1230.

    Article  CAS  Google Scholar 

  57. Lim JE, Kou J, Song M, Pattanayak A, Jin J, Lalonde R et al. MyD88 deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer's disease. Am J Pathol 2011; 179: 1095–1103.

    Article  CAS  Google Scholar 

  58. Michaud JP, Richard KL, Rivest S . MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. Mol Neurodegener 2011; 6: 5.

    Article  CAS  Google Scholar 

  59. Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 2008; 213: 114–121.

    Article  CAS  Google Scholar 

  60. Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB . Diabetes mellitus and Alzheimer's disease: shared pathology and treatment? Br J Clin Pharmacol 2011; 71: 365–376.

    Article  CAS  Google Scholar 

  61. Benarroch EE . Brain glucose transporters: implications for neurologic disease. Neurology 2014; 82: 1374–1379.

    Article  Google Scholar 

  62. Chen Z, Zhong C . Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 2013; 108: 21–43.

    Article  CAS  Google Scholar 

  63. Harris LW, Guest PC, Wayland MT, Umrania Y, Krishnamurthy D, Rahmoune H et al. Schizophrenia: metabolic aspects of aetiology, diagnosis and future treatment strategies. Psychoneuroendocrinology 2013; 38: 752–766.

    Article  CAS  Google Scholar 

  64. Steiner J, Bernstein HG, Schiltz K, Muller UJ, Westphal S, Drexhage HA et al. Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. Prog Neuropsychopharmacol Biol Psychiatry 2014; 48: 287–294.

    Article  CAS  Google Scholar 

  65. Garcia MC, Wernstedt I, Berndtsson A, Enge M, Bell M, Hultgren O et al. Mature-onset obesity in interleukin-1 receptor I knockout mice. Diabetes 2006; 55: 1205–1213.

    Article  CAS  Google Scholar 

  66. Davis CN, Mann E, Behrens MM, Gaidarova S, Rebek M, Rebek J Jr. et al. MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. Proc Natl Acad Sci USA 2006; 103: 2953–2958.

    Article  CAS  Google Scholar 

  67. Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A et al. Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 2010; 184: 3326–3330.

    Article  CAS  Google Scholar 

  68. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S . Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11: 115–122.

    Article  CAS  Google Scholar 

  69. Maitra SR, Wojnar MM, Lang CH . Alterations in tissue glucose uptake during the hyperglycemic and hypoglycemic phases of sepsis. Shock 2000; 13: 379–385.

    Article  CAS  Google Scholar 

  70. Ferreira JM, Burnett AL, Rameau GA . Activity-dependent regulation of surface glucose transporter-3. J Neurosci 2011; 31: 1991–1999.

    Article  CAS  Google Scholar 

  71. Perez-Alvarez A, Araque A . Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets 2013; 14: 1220–1224.

    Article  CAS  Google Scholar 

  72. Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T et al. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 2007; 32: 1106–1115.

    Article  CAS  Google Scholar 

  73. Donzis EJ, Tronson NC . Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences. Neurobiol Learn Mem 2014; 115: 68–77.

    Article  CAS  Google Scholar 

  74. Dunn AJ . Effects of cytokines and infections on brain neurochemistry. Clin Neurosci Res 2006; 6: 52–68.

    Article  CAS  Google Scholar 

  75. Felger JC, Lotrich FE . Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 2013; 246: 199–229.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr S Akira and Dr S Seino for giving us permission to use MyD88- and Kir6.2-deficient mice, respectively, and Dr P Yu and Dr B Liss for providing us with the corresponding breeding pairs. We also thank Dr F Pitossi for providing the IL-1ra adenovector, and N Özen and A Muth for excellent technical assistance. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG RE 1451/3-1) to AdR.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H O Besedovsky.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

del Rey, A., Verdenhalven, M., Lörwald, A. et al. Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner. Mol Psychiatry 21, 1309–1320 (2016). https://doi.org/10.1038/mp.2015.174

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.174

This article is cited by

Search

Quick links