NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model

Journal of Neuroinflammation

Lan Tan³  Jin-Tai Yu²  Meng-Meng Li⁵  Zhen Sun⁵  Ying Li⁴  Xiang-Fei Meng⁵  Teng Jiang³  Da-Wei Meng⁶  Hua Chen⁴  Meng-Shan Tan¹  Jian-Guo Zhang⁶  Chen-Chen Tan⁵ 

[1] College of Medicine and Pharmaceutics, Ocean University of China, No.5 Yushan Road, Qingdao 266003, China;Memory and Aging Center, Department of Neurology, University of California, San Francisco 94158, CA, USA;Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, No.5 Donghai Middle Road, Qingdao 266071, China;Department of Pathology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao 266071, China;Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, No.5 Donghai Middle Road, Qingdao 266071, China;Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.6, Tiantan Xili, Beijing 100050, China

关键词: temporal lobe epilepsy;    Caspase-1;    inflammasome;    pyroptosis;    NLRP1;   

Others  :  1149679
DOI  :  10.1186/s12974-014-0233-0

 received in 2014-10-21, accepted in 2014-12-28,  发布年份 2015

【 摘 要 】

Background

Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed ‘pyroptosis’, which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process.

Methods

We first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats.

Results

Western blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis.

Conclusions

Our data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.

【 授权许可】

   
2015 Tan et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Dericioglu N, Soylemezoglu F, Gursoy-Ozdemir Y, Akalan N, Saygi S, Dalkara T: Cell death and survival mechanisms are concomitantly active in the hippocampus of patients with mesial temporal sclerosis. Neuroscience 2013, 237:56-65.
• [2]Yamamoto A, Murphy N, Schindler CK, So NK, Stohr S, Taki W, et al.: Endoplasmic reticulum stress and apoptosis signaling in human temporal lobe epilepsy. J Neuropathol Exp Neurol 2006, 65:217-25.
• [3]Tan MS, Yu JT, Jiang T, Zhu XC, Tan L: The NLRP3 Inflammasome in Alzheimer's Disease. Mol Neurobiol 2013, 48:875-82.
• [4]Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O'Donnell JA, et al.: NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity 2012, 37:1009-23.
• [5]Bergsbaken T, Fink SL, Cookson BT: Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 2009, 7:99-109.
• [6]de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW: Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 2009, 29:1251-61.
• [7]Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD: Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 2009, 29:534-44.
• [8]Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, et al.: Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 2007, 55:443-52.
• [9]Fann DY, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, et al.: Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis 2013, 4:e790.
• [10]Vezzani A, French J, Bartfai T, Baram TZ: The role of inflammation in epilepsy. Nat Rev Neurol 2011, 7:31-40.
• [11]Kumar G, Mittal S, Moudgil SS, Kupsky WJ, Shah AK: Histopathological evidence that hippocampal atrophy following status epilepticus is a result of neuronal necrosis. J Neurol Sci 2013, 334:186-91.
• [12]Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al.: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010, 51:1069-77.
• [13]Bjorling DE, Wang ZY: Estrogen and neuroinflammation. Urology 2001, 57:40-6.
• [14]Sun Z, Yu JT, Jiang T, Li MM, Tan L, Zhang Q: Genome-wide microRNA profiling of rat hippocampus after status epilepticus induced by amygdala stimulation identifies modulators of neuronal apoptosis. PLoS ONE 2013, 8:e78375.
• [15]Li MM, Jiang T, Sun Z, Zhang Q, Tan CC, Yu JT, et al.: Genome-wide microRNA expression profiles in hippocampus of rats with chronic temporal lobe epilepsy. Sci Rep 2014, 4:4734.
• [16]Racine RJ: Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972, 32:281-94.
• [17]Thakker DR, Hoyer D, Cryan JF: Interfering with the brain: use of RNA interference for understanding the pathophysiology of psychiatric and neurological disorders. Pharmacol Ther 2006, 109:413-38.
• [18]Denes A, Lopez-Castejon G, Brough D: Caspase-1: is IL-1 just the tip of the ICEberg? Cell Death Dis 2012, 3:e338.
• [19]Levandowski CB, Mailloux CM, Ferrara TM, Gowan K, Ben S, Jin Y, et al.: NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1beta processing via the NLRP1 inflammasome. Proc Natl Acad Sci U S A 2013, 110:2952-6.
• [20]Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, et al.: Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 2013, 59:183-93.
• [21]Kovarova M, Hesker PR, Jania L, Nguyen M, Snouwaert JN, Xiang Z, et al.: NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J Immunol 2012, 189:2006-16.
• [22]Tan MS, Tan L, Jiang T, Zhu XC, Wang HF, Jia CD, et al.: Amyloid-beta induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease. Cell Death Dis 2014, 5:e1382.
• [23]Walsh JG, Muruve DA, Power C: Inflammasomes in the CNS. Nat Rev Neurosci 2014, 15:84-97.
• [24]Wasterlain CG, Niquet J, Thompson KW, Baldwin R, Liu H, Sankar R, et al.: Seizure-induced neuronal death in the immature brain. Prog Brain Res 2002, 135:335-53.
• [25]Steinhauser C, Seifert G, Bedner P: Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling. Glia 2012, 60:1192-202.
• [26]Arlehamn CS, Petrilli V, Gross O, Tschopp J, Evans TJ: The role of potassium in inflammasome activation by bacteria. J Biol Chem 2010, 285:10508-18.
• [27]Nissinen J, Halonen T, Koivisto E, Pitkanen A: A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res 2000, 38:177-205.
• [28]Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al.: Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009, 15:1170-8.
• [29]Cryan JF, Thakker DR, Hoyer D: Emerging use of non-viral RNA interference in the brain. Biochem Soc Trans 2007, 35:411-5.
• [30]Thakker DR, Natt F, Husken D, Maier R, Muller M, van der Putten H, et al.: Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference. Proc Natl Acad Sci U S A 2004, 101:17270-5.
• [31]Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, Nishimura M: Interleukin (IL)1beta, IL-1alpha, and IL-1 receptor antagonist gene polymorphisms in patients with temporal lobe epilepsy. Ann Neurol 2000, 47:571-4.
• [32]Maroso M, Balosso S, Ravizza T, Liu J, Bianchi M, Vezzani A: Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. J Intern Med 2011, 270:319.