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Nod-Like Receptor Protein 1 Inflammasome Mediates Neuron Injury under High Glucose

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Abstract

Diabetic encephalopathy is one of the most common complications of diabetes. Inflammatory events during diabetes may be an important mechanism of diabetic encephalopathy. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein (ASC), and caspase 1 or 5, which functions to switch on the inflammatory process and the release of inflammatory factors. The present study hypothesized that the formation and activation of NLRP1 inflammasome turns on neuroinflammation and neuron injury during hyperglycemia. The results demonstrated that the levels of interleukin-1 beta (IL-1β) were increased in the cortex of streptozocin (STZ)-induced diabetic rats. The levels of mature IL-1β and IL-18 were also elevated in culture medium of neurons treated with high glucose (50 mM). The expression of three essential components of the NLRP1 inflammasome complex, namely, NLRP1, ASC, and caspase 1, was also upregulated in vivo and in vitro under high glucose. Silencing the ASC gene prevented the caspase-1 activation, and inhibiting caspase 1 activity blocked hyperglycemia-induced release of inflammatory factors and neuron injury. Moreover, we found that pannexin 1 mediated the actvitation of NLRP1 inflammasome under high glucose. These results suggest that hyperglycemia induces neuroinflammation through activation of NLRP1 inflammasome, which represents a novel mechanism of diabetes-associated neuron injury.

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References

  1. Aachoui Y, Sagulenko V, Miao EA, Stacey KJ (2013) Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Curr Opin Microbiol 16(3):319–326

    Article  CAS  PubMed  Google Scholar 

  2. Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD (2009) Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 29(3):534–544

    Article  CAS  PubMed  Google Scholar 

  3. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW (2012) Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg 117(6):1119–1125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Aronson D (2008) Hyperglycemia and the pathobiology of diabetic complications. Adv Cardiol 45:1–16

    Article  CAS  PubMed  Google Scholar 

  5. Benchoua A, Braudeau J, Reis A, Couriaud C, Onteniente B (2004) Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia. J Cereb Blood Flow Metab 24(11):1272–1279

    Article  CAS  PubMed  Google Scholar 

  6. Bennett MV, Garre JM, Orellana JA, Bukauskas FF, Nedergaard M, Saez JC (2012) Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res 1487:3–15

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y, Quesniaux V, Ryffel B, Togbe D (2011) NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy 66(8):1047–1057

    Article  CAS  PubMed  Google Scholar 

  8. Brough D, Pelegrin P, Rothwell NJ (2009) Pannexin-1-dependent caspase-1 activation and secretion of IL-1beta is regulated by zinc. Eur J Immunol 39(2):352–358

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Carta S, Castellani P, Delfino L, Tassi S, Vene R, Rubartelli A (2009) DAMPs and inflammatory processes: the role of redox in the different outcomes. J Leukoc Biol 86(3):549–555

    Article  CAS  PubMed  Google Scholar 

  10. Damiano JS, Reed JC (2004) CARD proteins as therapeutic targets in cancer. Curr Drug Targets 5(4):367–374

    Article  CAS  PubMed  Google Scholar 

  11. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW (2009) Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29(7):1251–1261

    Article  PubMed Central  PubMed  Google Scholar 

  12. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW (2008) A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci 28(13):3404–3414

    Article  PubMed  Google Scholar 

  13. Edwards JL, Vincent AM, Cheng HT, Feldman EL (2008) Diabetic neuropathy: mechanisms to management. Pharmacol Ther 120(1):1–34

    Article  CAS  PubMed  Google Scholar 

  14. Fazeli SA (2009) Neuroprotection in diabetic encephalopathy. Neurodegener Dis 6(5–6):213–218

    Article  PubMed  Google Scholar 

  15. Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF (2005) IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 28(9):487–493

    Article  CAS  PubMed  Google Scholar 

  16. Fischer AE, Dolger H (1946) Behavior and psychologic problems of young diabetic patients; a ten to twenty year survey. Arch Intern Med (Chic) 78(6):711–732

    Article  CAS  Google Scholar 

  17. Gattorno M, La Regina M, Martini A, Manna R (2009) An update on autoinflammatory diseases. New concepts for new and old diseases. Clin Exp Rheumatol 27(2):354–365

    CAS  PubMed  Google Scholar 

  18. Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O’Banion MK (2013) Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 33(11):5053–5064

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Grant RW, Dixit VD (2013) Mechanisms of disease: inflammasome activation and the development of type 2 diabetes. Front Immunol 4:50

    Article  PubMed Central  PubMed  Google Scholar 

  20. Gulbransen BD, Bashashati M, Hirota SA, Gui X, Roberts JA, MacDonald JA, Muruve DA, McKay DM, Beck PL, Mawe GM, Thompson RJ, Sharkey KA (2012) Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nat Med 18(4):600–604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA (1997) Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A 94(5):2007–2012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Hitzler I, Sayi A, Kohler E, Engler DB, Koch KN, Hardt WD, Muller A (2012) Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1beta and IL-18. J Immunol 188(8):3594–3602

    Article  CAS  PubMed  Google Scholar 

  23. Ifuku M, Katafuchi T, Mawatari S, Noda M, Miake K, Sugiyama M, Fujino T (2012) Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice. J Neuroinflammation 9:197

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA (2007) NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 356(12):1216–1225

    Article  CAS  PubMed  Google Scholar 

  25. Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A (2013) Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol 698(1–3):259–266

    Article  CAS  PubMed  Google Scholar 

  26. Kodl CT, Seaquist ER (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29(4):494–511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Kuhad A, Bishnoi M, Tiwari V, Chopra K (2009) Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 92(2):251–259

    Article  CAS  PubMed  Google Scholar 

  28. Kuhad A, Chopra K (2007) Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol 576(1–3):34–42

    Article  CAS  PubMed  Google Scholar 

  29. Leinninger GM, Backus C, Sastry AM, Yi YB, Wang CW, Feldman EL (2006) Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1. Neurobiol Dis 23(1):11–22

    Article  CAS  PubMed  Google Scholar 

  30. Li ZG, Zhang W, Grunberger G, Sima AA (2002) Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946(2):221–231

    Article  CAS  PubMed  Google Scholar 

  31. Liu ZJ, Liu W, Liu L, Xiao C, Wang Y, Jiao JS (2013) Curcumin protects neuron against cerebral ischemia-induced inflammation through improving PPAR-gamma function. Evid Based Complement Alternat Med 2013:470975

    PubMed Central  PubMed  Google Scholar 

  32. Liu F, Lo CF, Ning X, Kajkowski EM, Jin M, Chiriac C, Gonzales C, Naureckiene S, Lock YW, Pong K, Zaleska MM, Jacobsen JS, Silverman S, Ozenberger BA (2004) Expression of NALP1 in cerebellar granule neurons stimulates apoptosis. Cell Signal 16(9):1013–1021

    Article  CAS  PubMed  Google Scholar 

  33. Luchsinger JA (2012) Type 2 diabetes and cognitive impairment: linking mechanisms. J Alzheimers Dis 30(Suppl 2):S185–S198

    PubMed Central  PubMed  Google Scholar 

  34. Luksch H, Romanowski MJ, Chara O, Tungler V, Caffarena ER, Heymann MC, Lohse P, Aksentijevich I, Remmers EF, Flecks S, Quoos N, Gramatte J, Petzold C, Hofmann SR, Winkler S, Pessler F, Kallinich T, Ganser G, Nimtz-Talaska A, Baumann U, Runde V, Grimbacher B, Birmelin J, Gahr M, Roesler J, Rosen-Wolff A (2013) Naturally occurring genetic variants of human caspase-1 differ considerably in structure and the ability to activate interleukin-1beta. Hum Mutat 34(1):122–131

    Article  CAS  PubMed  Google Scholar 

  35. Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O’Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT, Croker BA (2012) NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 37(6):1009–1023

    Article  CAS  PubMed  Google Scholar 

  36. Mayfield J (1998) Diagnosis and classification of diabetes mellitus: new criteria. Am Fam Physician 58(6):1355–1362, 1369–1370

    CAS  PubMed  Google Scholar 

  37. Meek TH, Morton GJ (2012) Leptin, diabetes, and the brain. Indian J Endocrinol Metab 16(Suppl 3):S534–S542

    PubMed Central  PubMed  Google Scholar 

  38. Pelegrin P (2008) Targeting interleukin-1 signaling in chronic inflammation: focus on P2X(7) receptor and Pannexin-1. Drug News Perspect 21(8):424–433

    CAS  PubMed  Google Scholar 

  39. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25(21):5071–5082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ravizza T, Lucas SM, Balosso S, Bernardino L, Ku G, Noe F, Malva J, Randle JC, Allan S, Vezzani A (2006) Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia 47(7):1160–1168

    Article  CAS  PubMed  Google Scholar 

  41. Rigato C, Swinnen N, Buckinx R, Couillin I, Mangin JM, Rigo JM, Legendre P, Le Corronc H (2012) Microglia proliferation is controlled by P2X7 receptors in a Pannexin-1-independent manner during early embryonic spinal cord invasion. J Neurosci 32(34):11559–11573

    Article  CAS  PubMed  Google Scholar 

  42. Russell JW, Golovoy D, Vincent AM, Mahendru P, Olzmann JA, Mentzer A, Feldman EL (2002) High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J 16(13):1738–1748

    Article  CAS  PubMed  Google Scholar 

  43. Sharma R, Buras E, Terashima T, Serrano F, Massaad CA, Hu L, Bitner B, Inoue T, Chan L, Pautler RG (2010) Hyperglycemia induces oxidative stress and impairs axonal transport rates in mice. PLoS ONE 5(10):e13463

    Article  PubMed Central  PubMed  Google Scholar 

  44. Sima AA (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47(4):279–293

    Article  CAS  PubMed  Google Scholar 

  45. Sima AA, Zhang W, Kreipke CW, Rafols JA, Hoffman WH (2009) Inflammation in diabetic encephalopathy is prevented by C-peptide. Rev Diabet Stud 6(1):37–42

    Article  PubMed Central  PubMed  Google Scholar 

  46. Sollberger G, Strittmatter GE, Garstkiewicz M, Sand J, Beer HD (2013) Caspase-1: the inflammasome and beyond. Innate Immunity

  47. Tomura S, de Rivero Vaccari JP, Keane RW, Bramlett HM, Dietrich WD (2012) Effects of therapeutic hypothermia on inflammasome signaling after traumatic brain injury. J Cereb Blood Flow Metab 32(10):1939–1947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Tschopp J, Schroder K (2010) NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 10(3):210–215

    Article  CAS  PubMed  Google Scholar 

  49. Umegaki H (2012) Neurodegeneration in diabetes mellitus. Adv Exp Med Biol 724:258–265

    Article  CAS  PubMed  Google Scholar 

  50. Vargas R, Rincon J, Pedreanez A, Viera N, Hernandez-Fonseca JP, Pena C, Mosquera J (2012) Role of angiotensin II in the brain inflammatory events during experimental diabetes in rats. Brain Res 1453:64–76

    Article  CAS  PubMed  Google Scholar 

  51. Vincent AM, Brownlee M, Russell JW (2002) Oxidative stress and programmed cell death in diabetic neuropathy. Ann N Y Acad Sci 959:368–383

    Article  CAS  PubMed  Google Scholar 

  52. Wang X, Song Y, Chen L, Zhuang G, Zhang J, Li M, Meng XF (2013) Contribution of single-minded 2 to hyperglycaemia-induced neurotoxicity. Neurotoxicology 35:106–112

    Article  CAS  PubMed  Google Scholar 

  53. Xu XJ, Boumechache M, Robinson LE, Marschall V, Gorecki DC, Masin M, Murrell-Lagnado RD (2012) Splice variants of the P2X7 receptor reveal differential agonist dependence and functional coupling with pannexin-1. J Cell Sci 125(Pt 16):3776–3789

    Article  CAS  PubMed  Google Scholar 

  54. Yang RH, Wang F, Hou XH, Cao ZP, Wang B, Xu XN, Hu SJ (2012) Dietary omega-3 polyunsaturated fatty acids improves learning performance of diabetic rats by regulating the neuron excitability. Neuroscience 212:93–103

    Article  CAS  PubMed  Google Scholar 

  55. Ye L, Wang F, Yang RH (2011) Diabetes impairs learning performance and affects the mitochondrial function of hippocampal pyramidal neurons. Brain Res 1411:57–64

    Article  CAS  PubMed  Google Scholar 

  56. Yin Y, Pastrana JL, Li X, Huang X, Mallilankaraman K, Choi ET, Madesh M, Wang H, Yang XF (2013) Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci 18:638–649

    Article  CAS  Google Scholar 

  57. Zhang L, Deng T, Sun Y, Liu K, Yang Y, Zheng X (2008) Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation. J Neurosci Res 86(10):2281–2291

    Article  CAS  PubMed  Google Scholar 

  58. Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci U S A 100(26):16012–16017

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Zhang X, Xu L, He D, Ling S (2013) Endoplasmic reticulum stress-mediated hippocampal neuron apoptosis involved in diabetic cognitive impairment. Biomed Res Int 2013:924327

    PubMed Central  PubMed  Google Scholar 

  60. Zhang WF, Xu YY, Xu KP, Wu WH, Tan GS, Li YJ, Hu CP (2012) Inhibitory effect of selaginellin on high glucose-induced apoptosis in differentiated PC12 cells: role of NADPH oxidase and LOX-1. Eur J Pharmacol 694(1–3):60–68

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81170600 and 81170662), the Natural Science Foundation of Hubei Province (2011CDB362), and the Innovation Foundation of Huazhong University of Science and Technology (No. 2011QN215).

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Authors and Affiliations

  1. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xian-Fang Meng, Xiao-Lan Wang, Zhi-Hua Yang, Guang-Pin Chu, Jing Zhang, Man Li & Jing Shi

  2. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiu-Juan Tian & Chun Zhang

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  1. Xian-Fang Meng
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Correspondence to Chun Zhang.

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Supplemental Fig. 1

Effects of mannitol on IL-1β and IL-18 processi in cultured neurons. Neurons were cultured for at least 6 days and then treated with 25 mM mannitol. It was shown that the secretion of IL-1β and Il-18 was unchanged at 25 mM mannitol with 25 mM glucose. n = 5 per group. Data are presented as mean ± SEM. (DOC 36 kb)

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Meng, XF., Wang, XL., Tian, XJ. et al. Nod-Like Receptor Protein 1 Inflammasome Mediates Neuron Injury under High Glucose. Mol Neurobiol 49, 673–684 (2014). https://doi.org/10.1007/s12035-013-8551-2

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