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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment

Authors: Zhi Wang, Shiyu Meng, Lin Cao, Ying Chen, Zhiyi Zuo, Shuling Peng

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Elderly patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia. Except for declined organ function, the particular pathogenesis of POCD in elderly patients remains unknown. This study is carried out to determine the critical role of the NOD-like receptor protein 3 (NLRP3)-caspase-1 pathway in isoflurane-induced cognitive impairment.

Methods

Young (6–8 months old) and aged (14 months old) healthy male C57BL/6 mice were exposed to 1.5% isoflurane for 2 h. Some mice received intraperitoneal injection of Ac-YVAD-cmk (8 mg/kg), a specific inhibitor of caspase-1, 30 min before the isoflurane exposure. Morris water maze test was carried out 1 week after the isoflurane anesthesia. Brain tissues were harvested 24 h after the isoflurane anesthesia. Western blotting was carried out to detect the expression of NLRP3, interleukin (IL)-1β, and IL-18 in the hippocampus. Mouse microglial cell line BV-2 and primary microglial cultures were primed by lipopolysaccharide for 30 min before being exposed to isoflurane. NLRP3 was downregulated by RNA interference.

Results

Compared to young mice, aged mice had an increased expression of NLRP3 in the hippocampus. Isoflurane induced cognitive impairment and hippocampal inflammation in aged mice but not in young mice. These effects were attenuated by Ac-YVAD-cmk pretreatment (P < 0.05). Isoflurane activated NLRP3-caspase-1 pathway and increased the secretion of IL-18 and IL-1β in cells pretreated with lipopolysaccharide but not in cells without pretreatment. Downregulation of NLRP3 attenuated the activation of NLRP3 inflammasome by isoflurane.

Conclusions

NLRP3 priming status in aged mouse brain may be involved in isoflurane-induced hippocampal inflammation and cognitive impairment.
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Literature
1.
Akbaraly TN, Hamer M, Ferrie JE, Lowe G, Batty GD, Hagger-Johnson G, Singh-Manoux A, Shipley MJ, Kivimaki M. Chronic inflammation as a determinant of future aging phenotypes. CMAJ. 2013;185:E763.CrossRefPubMedPubMedCentral
2.
Bittner EA, Yue Y, Xie Z. Brief review: anesthetic neurotoxicity in the elderly, cognitive dysfunction and Alzheimer’s disease. Can J Anaesth. 2011;58:216.CrossRefPubMed
3.
4.
Terrando N, Eriksson LI, Kyu Ryu J, Yang T, Monaco C, Feldmann M, Jonsson Fagerlund M, Charo IF, Akassoglou K, Maze M. Resolving postoperative neuroinflammation and cognitive decline. Ann Neurol. 2011;70:986.CrossRefPubMedPubMedCentral
5.
Zuo Z. Postoperative cognitive effects in newborns: the role of inflammatory processes. Anesthesiology. 2013;118:481.CrossRefPubMed
6.
Zhang Z, Li X, Li F, An L. Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice. Int Immunopharmacol. 2016;38:426.CrossRefPubMed
7.
Hovens IB, van Leeuwen BL, Nyakas C, Heineman E, van der Zee EA, Schoemaker RG. Postoperative cognitive dysfunction and microglial activation in associated brain regions in old rats. Neurobiol Learn Mem. 2015;118:74.CrossRefPubMed
8.
Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244.CrossRefPubMed
9.
Goto M. Inflammaging (inflammation + aging): a driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci Trends. 2008;2:218.PubMed
10.
Koellhoffer EC, McCullough LD, Ritzel RM. Old maids: aging and its impact on microglia function. Int J Mol Sci. 2017;18:e769
11.
12.
13.
14.
Ji M, Dong L, Jia M, Liu W, Zhang M, Ju L, Yang J, Xie Z, Yang J. Epigenetic enhancement of brain-derived neurotrophic factor signaling pathway improves cognitive impairments induced by isoflurane exposure in aged rats. Mol Neurobiol. 2014;50:937.CrossRefPubMedPubMedCentral
15.
Lin D, Cao L, Wang Z, Li J, Washington JM, Zuo Z. Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats. Behav Brain Res. 2012;228:319.CrossRefPubMed
16.
Li X, Zhou M, Wang X, Ji M, Zhou Z, Yang J. Resveratrol pretreatment attenuates the isoflurane-induced cognitive impairment through its anti-inflammation and -apoptosis actions in aged mice. J Mol Neurosci. 2014;52:286.CrossRefPubMed
17.
18.
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14:463.CrossRefPubMed
19.
20.
Youm Y, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 2013;18:519.CrossRefPubMedPubMedCentral
21.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng T, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2012;493:674.CrossRefPubMedPubMedCentral
22.
23.
Zhuang J, Wen X, Zhang YQ, Shan Q, Zhang ZF, Zheng GH, Fan SH, Li MQ, Wu DM, Hu B, Lu J, Zheng YL. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2 2′,4,4′-tetrabromodiphenyl ether (BDE-47)-treated mice. Brain Behav Immun. 2017;65:99.CrossRefPubMed
24.
25.
26.
Abais JM, Xia M, Zhang Y, Boini KM, Li P. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Sign. 2015;22:1111.
27.
Zhang F, Wang L, Wang J, Luo P, Wang X, Xia Z. The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities. Sci Rep. 2016;6:24166.
28.
Pan K, Li X, Chen Y, Zhu D, Li Y, Tao G, Zuo Z. Deferoxamine pre-treatment protects against postoperative cognitive dysfunction of aged rats by depressing microglial activation via ameliorating iron accumulation in hippocampus. Neuropharmacology. 2016;111:180.CrossRefPubMed
29.
Johnson T, Monk T, Rasmussen LS, Abildstrom H, Houx P, Korttila K, Kuipers HM, Hanning CD, Siersma VD, Kristensen D, Canet J, Ibanaz MT, Moller JT. Postoperative cognitive dysfunction in middle-aged patients. Anesthesiology. 2002;96:1351.CrossRefPubMed
30.
Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M. Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol. 2010;68:360.CrossRefPubMedPubMedCentral
31.
32.
Zhang L, Zhang J, Yang L, Dong Y, Zhang Y, Xie Z. Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells. Brit J Anaesth. 2013;110:i82.CrossRefPubMedPubMedCentral
33.
Schallner N, Ulbrich F, Engelstaedter H, Biermann J, Auwaerter V, Loop T, Goebel U. Isoflurane but not sevoflurane or desflurane aggravates injury to neurons in vitro and in vivo via p75NTR-NF-kB activation. Anesth Analg. 2014;119:1429.CrossRefPubMed
34.
Eckel B, Richtsfeld M, Starker L, Blobner M. Transgenic Alzheimer mice have a larger minimum alveolar anesthetic concentration of isoflurane than their nontransgenic littermates. Anesth Analg. 2010;110:438.CrossRefPubMed
35.
Wu J, Li H, Sun X, Zhang H, Hao S, Ji M, Yang J, Li K. A mitochondrion-targeted antioxidant ameliorates isoflurane-induced cognitive deficits in aging mice. PLoS One. 2015;10:e138256.
36.
Tanino M, Kobayashi M, Sasaki T, Takata K, Takeda Y, Mizobuchi S, Morita K, Nagai T, Morimatsu H. Isoflurane induces transient impairment of retention of spatial working memory in rats. Acta Med Okayama. 2016;70:455.PubMed
37.
Wu X, Lu Y, Dong Y, Zhang G, Zhang Y, Xu Z, Culley DJ, Crosby G, Marcantonio ER, Tanzi RE, Xie Z. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiol Aging. 2012;33:1364.CrossRefPubMed
38.
Fougere B, Boulanger E, Nourhashemi F, Guyonnet S, Cesari M. Chronic inflammation: accelerator of biological aging. J Gerontol A Biol Sci Med Sci. 2016;72:1218.
39.
Fernandes A, Miller-Fleming L, Pais TF. Microglia and inflammation: conspiracy, controversy or control? Cell Mol Life Sci. 2014;71:3969.CrossRefPubMed
40.
Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropath Appl Neuro. 2013;39:19.CrossRef
41.
Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2015;53:1181.
42.
Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P, Dostert C. NLRP3 Inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 2015;10:e130624.
43.
44.
Trott DW, Henson GD, Ho MH, Allison SA, Lesniewski LA, Donato AJ. Age-related arterial immune cell infiltration in mice is attenuated by caloric restriction or voluntary exercise. Exp Gerontol. 2016;(16)30348-5.
45.
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL. Identification of a unique TGF-β–dependent molecular and functional signature in microglia. Nat Neurosci. 2013;17:131.CrossRefPubMedPubMedCentral
46.
Weber MD, Frank MG, Tracey KJ, Watkins LR, Maier SF. Stress induces the danger-associated molecular pattern HMGB-1 in the Hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 Inflammasome. J Neurosci. 2015;35:316.CrossRefPubMedPubMedCentral
47.
You T, Cheng Y, Zhong J, Bi B, Zeng B, Zheng W, Wang H, Xu J. Roflupram, a phosphodiesterase 4 inhibitior, suppresses inflammasome activation through autophagy in microglial cells. ACS Chem Neurosci. 2017;8:2381.
48.
Yang H, Chen Y, Yu L, Xu Y. Esculentoside a exerts anti-inflammatory activity in microglial cells. Int Immunopharmacol. 2017;51:148.CrossRefPubMed
49.
Kaushal V, Dye R, Pakavathkumar P, Foveau B, Flores J, Hyman B, Ghetti B, Koller BH, LeBlanc AC. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015;22:1676.CrossRefPubMedPubMedCentral
Metadata
Title
Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment
Authors
Zhi Wang
Shiyu Meng
Lin Cao
Ying Chen
Zhiyi Zuo
Shuling Peng
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1137-1

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