NLRP3 炎症小体与癫痫的研究进展_Journal of Epilepsy

Authors：

廖勇 ^1,2 , 董继波 ¹ , 舒鹏 ¹ ,  吴碧华 ¹

1. ;
2. ;

Corresponding author：

吴碧华, Email: bhua100@163.com

Keywords：

NLRP3; 癫痫; 白介素-1β; 炎症

DOI：

10.7507/2096-0247.20210087

Video：

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癫痫是一种常见的慢性脑部神经元异常放电的疾病。癫痫的发病机制复杂，与神经元递质效失衡、离子通道异常、神经网络重构及颅内炎症激活等密切相关。癫痫与炎症炎症与癫痫关系密切，癫痫会促使颅内炎症发生，而炎症会进一步加重癫痫。作为重要的炎性小体，核苷酸结合寡聚化结构域样受体蛋白 3（NLPR3）激活后促使炎症效应因子释放，加重癫痫发作，是近年来研究热点。本文就 NLRP3 炎性小体与癫痫的关系进行综述，以期从炎症角度阐明两者之间的关系，为究癫痫的防治提供新思路。

Citation： 廖勇, 董继波, 舒鹏, 吴碧华. NLRP3 炎症小体与癫痫的研究进展. Journal of Epilepsy, 2021, 7(6): 525-529. doi: 10.7507/2096-0247.20210087 Copy

1.	Kundap UP, Paudel YN, Shaikh MF. Animal models of metabolic epilepsy and epilepsy associated metabolic dysfunction: A systematic review. Pharmaceuticals (Basel), 2020, 13(6): 106.
2.	Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. 2019, 16, 393(10172): 689-701.
3.	Huajun Y, Anchen G, Qun WJE, et al. Advances in pathogenesis of epilepsy, 2017, 35(4): 54-59.
4.	Ko Y, Lee C, Lee Y, et al. Systematic approach for drug repositioning of anti-epileptic drugs. Diagnostics (Basel), 2019, 9(4): 256-261.
5.	Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 2018, 17(8): 588-606.
6.	Vezzani A, Lang B, Aronica E. Immunity and inflammation in epilepsy. Cold Spring Harb Perspect Med, 2015, 6(2): a022699.
7.	Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol, 2019, 19(8): 477-489.
8.	Wang Z, Meng S, Cao L, et al. Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment. J Neuroinflammation, 2018, 15(1): 109.
9.	Fleshner M, Frank M, Maier SF. Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology, 2017, 42(1): 36-45.
10.	Grebe A, Hoss F, Latz E. NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ Res, 2018, 122(12): 1722-1740.
11.	Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol, 2009, 183(2): 787-91.
12.	Zeng QZ, Yang F, Li CG, et al. Paclitaxel enhances the innate immunity by promoting NLRP3 inflammasome activation in macrophages. Front Immunol, 2019, 10: 72.
13.	Burnstock G. P2X ion channel receptors and inflammation. Purinergic Signal, 2016, 12(1): 59-67.
14.	Hudson G, Flannigan KL, Venu VKP, et al. Pregnane X receptor activation triggers rapid ATP release in primed macrophages that mediates NLRP3 inflammasome activation. J Pharmacol Exp Ther, 2019, 370(1): 44-53.
15.	Di A, Xiong S, Ye Z, et al. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity, 2018, 49(1): 56-65.
16.	Zhou K, Enkhjargal B, Xie Z, et al. Dihydrolipoic acid inhibits lysosomal rupture and NLRP3 through lysosome-associated membrane protein-1/calcium/calmodulin-dependent protein kinase II/TAK1 pathways after subarachnoid hemorrhage in rat. Stroke, 2018, 49(1): 175-183.
17.	Du RH, Wu FF, Lu M, et al. Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depressio. Immunity, 2016, 9(C): 178-187.
18.	Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 2012, 36(3): 401-414.
19.	Abdelaziz DH, Khalil H, Cormet-Boyaka E, et al. The cooperation between the autophagy machinery and the inflammasome to implement an appropriate innate immune response: do they regulate each other? Immunol Rev, 2015, 265(1): 194-204.
20.	Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 2002, 10(2): 417-426.
21.	Abais, Justine, M. , et al. Inflammasome activation in chronic glomerular diseases. Sci Rep, 2017, 18: 1019-1029.
22.	Long Y, Liu X, Tan XZ, et al. ROS-induced NLRP3 inflammasome priming and activation mediate PCB 118- induced pyroptosis in endothelial cells. Ecotoxicol Environ Saf, 2020, 189: 109937.
23.	Wu X, Zhang H, Qi W, et al. Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis, 2018, 9(2): 171.
24.	Tsai YL, Hua KF, Chen A, et al. NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy. Sci Rep, 2017, 7: 41123.
25.	Komada T, Muruve DA. The role of inflammasomes in kidney disease. Nat Rev Nephrol, 2019, 15(8): 501-520.
26.	Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature, 2019, 575(7784): 669-673.
27.	Stancu IC, Cremers N, Vanrusselt H, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol, 2019, 137(4): 599-617.
28.	Skaper SD, Laura F, Morena Z, et al. An inflammation-centric view of neurological disease: beyond the neuron. Sci Rep, 2018, 12: 72.
29.	Meng XF, Tan L, Tan MS, et al. Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. J Neuroinflammation, 2014, 11: 212.
30.	Rong S, Wan D, Fan Y, et al. Amentoflavone affects epileptogenesis and exerts neuroprotective effects by inhibiting NLRP3 inflammasome. Front Pharmacol, 2019, 10: 856.
31.	Wu C, Zhang G, Chen L, et al. The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury. Front Neurol, 2019, 10: 1418.
32.	Fang G, Neurology D O J a M S. Effect of Celecoxib combined with Carbamazepine on epilepsy patients and inflammatory factors in serum. Sci Rep, 2018, 06: 0073.
33.	Mendiola AS, Cardona AE. The IL-1β phenomena in neuroinflammatory diseases. J Neural Transm (Vienna), 2018, 125(5): 781-795.
34.	Xiao Z, Peng J, Wu L, et al. The effect of IL-1β on synaptophysin expression and electrophysiology of hippocampal neurons through the PI3K/Akt/mTOR signaling pathway in a rat model of mesial temporal lobe epilepsy. Neurol Res, 2017, 39(7): 640-648.
35.	Feng B, Tang Y, Chen B, et al. Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling. Sci Rep, 2016, 6: 21931.
36.	Barseem NF, Khattab E, Mahasab MM. IL-1β-31/IL1-RA genetic markers association with idiopathic generalized epilepsy and treatment response in a cohort of Egyptian population. Int J Neurosci, 2020, 130(4): 348-354.
37.	Peiró C, Lorenzo Ó, Carraro R, et al. IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus. Front Pharmacol, 2017, 8: 363.
38.	He Q, Jiang L, Man S, et al. Curcumin reduces neuronal loss and inhibits the NLRP3 inflammasome activation in an epileptic rat model. Curr Neurovasc Res, 2018, 15(3): 186-192.
39.	Jiang H, He H, Chen Y, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med, 2017, 214(11): 3219-3238.
40.	Shen K, Jiang W, Zhang C, et al. Molecular mechanism of a specific NLRP3 inhibitor to alleviate seizure severity induced by pentylenetetrazole. Curr Mol Pharmacol, 2020, 13: 1205-1209.

1. Kundap UP, Paudel YN, Shaikh MF. Animal models of metabolic epilepsy and epilepsy associated metabolic dysfunction: A systematic review. Pharmaceuticals (Basel), 2020, 13(6): 106.
2. Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. 2019, 16, 393(10172): 689-701.
3. Huajun Y, Anchen G, Qun WJE, et al. Advances in pathogenesis of epilepsy, 2017, 35(4): 54-59.
4. Ko Y, Lee C, Lee Y, et al. Systematic approach for drug repositioning of anti-epileptic drugs. Diagnostics (Basel), 2019, 9(4): 256-261.
5. Mangan MSJ, Olhava EJ, Roush WR, et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 2018, 17(8): 588-606.
6. Vezzani A, Lang B, Aronica E. Immunity and inflammation in epilepsy. Cold Spring Harb Perspect Med, 2015, 6(2): a022699.
7. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol, 2019, 19(8): 477-489.
8. Wang Z, Meng S, Cao L, et al. Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment. J Neuroinflammation, 2018, 15(1): 109.
9. Fleshner M, Frank M, Maier SF. Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology, 2017, 42(1): 36-45.
10. Grebe A, Hoss F, Latz E. NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ Res, 2018, 122(12): 1722-1740.
11. Bauernfeind FG, Horvath G, Stutz A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol, 2009, 183(2): 787-91.
12. Zeng QZ, Yang F, Li CG, et al. Paclitaxel enhances the innate immunity by promoting NLRP3 inflammasome activation in macrophages. Front Immunol, 2019, 10: 72.
13. Burnstock G. P2X ion channel receptors and inflammation. Purinergic Signal, 2016, 12(1): 59-67.
14. Hudson G, Flannigan KL, Venu VKP, et al. Pregnane X receptor activation triggers rapid ATP release in primed macrophages that mediates NLRP3 inflammasome activation. J Pharmacol Exp Ther, 2019, 370(1): 44-53.
15. Di A, Xiong S, Ye Z, et al. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity, 2018, 49(1): 56-65.
16. Zhou K, Enkhjargal B, Xie Z, et al. Dihydrolipoic acid inhibits lysosomal rupture and NLRP3 through lysosome-associated membrane protein-1/calcium/calmodulin-dependent protein kinase II/TAK1 pathways after subarachnoid hemorrhage in rat. Stroke, 2018, 49(1): 175-183.
17. Du RH, Wu FF, Lu M, et al. Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depressio. Immunity, 2016, 9(C): 178-187.
18. Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity, 2012, 36(3): 401-414.
19. Abdelaziz DH, Khalil H, Cormet-Boyaka E, et al. The cooperation between the autophagy machinery and the inflammasome to implement an appropriate innate immune response: do they regulate each other? Immunol Rev, 2015, 265(1): 194-204.
20. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 2002, 10(2): 417-426.
21. Abais, Justine, M. , et al. Inflammasome activation in chronic glomerular diseases. Sci Rep, 2017, 18: 1019-1029.
22. Long Y, Liu X, Tan XZ, et al. ROS-induced NLRP3 inflammasome priming and activation mediate PCB 118- induced pyroptosis in endothelial cells. Ecotoxicol Environ Saf, 2020, 189: 109937.
23. Wu X, Zhang H, Qi W, et al. Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis, 2018, 9(2): 171.
24. Tsai YL, Hua KF, Chen A, et al. NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy. Sci Rep, 2017, 7: 41123.
25. Komada T, Muruve DA. The role of inflammasomes in kidney disease. Nat Rev Nephrol, 2019, 15(8): 501-520.
26. Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature, 2019, 575(7784): 669-673.
27. Stancu IC, Cremers N, Vanrusselt H, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol, 2019, 137(4): 599-617.
28. Skaper SD, Laura F, Morena Z, et al. An inflammation-centric view of neurological disease: beyond the neuron. Sci Rep, 2018, 12: 72.
29. Meng XF, Tan L, Tan MS, et al. Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. J Neuroinflammation, 2014, 11: 212.
30. Rong S, Wan D, Fan Y, et al. Amentoflavone affects epileptogenesis and exerts neuroprotective effects by inhibiting NLRP3 inflammasome. Front Pharmacol, 2019, 10: 856.
31. Wu C, Zhang G, Chen L, et al. The Role of NLRP3 and IL-1β in Refractory Epilepsy Brain Injury. Front Neurol, 2019, 10: 1418.
32. Fang G, Neurology D O J a M S. Effect of Celecoxib combined with Carbamazepine on epilepsy patients and inflammatory factors in serum. Sci Rep, 2018, 06: 0073.
33. Mendiola AS, Cardona AE. The IL-1β phenomena in neuroinflammatory diseases. J Neural Transm (Vienna), 2018, 125(5): 781-795.
34. Xiao Z, Peng J, Wu L, et al. The effect of IL-1β on synaptophysin expression and electrophysiology of hippocampal neurons through the PI3K/Akt/mTOR signaling pathway in a rat model of mesial temporal lobe epilepsy. Neurol Res, 2017, 39(7): 640-648.
35. Feng B, Tang Y, Chen B, et al. Transient increase of interleukin-1β after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling. Sci Rep, 2016, 6: 21931.
36. Barseem NF, Khattab E, Mahasab MM. IL-1β-31/IL1-RA genetic markers association with idiopathic generalized epilepsy and treatment response in a cohort of Egyptian population. Int J Neurosci, 2020, 130(4): 348-354.
37. Peiró C, Lorenzo Ó, Carraro R, et al. IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus. Front Pharmacol, 2017, 8: 363.
38. He Q, Jiang L, Man S, et al. Curcumin reduces neuronal loss and inhibits the NLRP3 inflammasome activation in an epileptic rat model. Curr Neurovasc Res, 2018, 15(3): 186-192.
39. Jiang H, He H, Chen Y, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med, 2017, 214(11): 3219-3238.
40. Shen K, Jiang W, Zhang C, et al. Molecular mechanism of a specific NLRP3 inhibitor to alleviate seizure severity induced by pentylenetetrazole. Curr Mol Pharmacol, 2020, 13: 1205-1209.

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