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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons

Authors: Yu-Chan Wang, Wei-Zu Li, Yu Wu, Yan-Yan Yin, Liu-Yi Dong, Zhi-Wu Chen, Wen-Ning Wu

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Acid-sensing ion channels (ASICs) are cation channels which were activated by extracellular acidosis and involved in various physiological and pathological processes in the nervous system. Inflammasome is a key component of the innate immune response in host against harmful and irritable stimuli. As the first discovered molecular platform, NLRP1 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 1) inflammasome is expressed in neurons and implicated in many nervous system diseases such as brain injury, nociception and epilepsy. However, little is known about the effect of ASICs on NLRP1 inflammasome activation under acidosis.

Methods

The expression of inflammasome complex protein (NLRP1, ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain) and caspase-1), inflammatory cytokines (IL-1β and IL-18), and apoptosis-related protein (Bax, Bcl-2, and activated caspase-3) was detected by Western blot. Large-conductance Ca2+ and voltage-activated K+ (BK) channel currents were recorded by whole-cell patch-clamp technology. Measurement of [K+] i was performed by fluorescent ion imaging system. Co-expression of ASICs and BK channels was determined by dual immunofluorescence. Cell viability was assessed by MTT and LDH kit.

Results

ASICs and BK channels were co-expressed in primary cultured cortical neurons. Extracellular acidosis increased the expression of NLRP1, ASC, caspase-1, IL-1β, and IL-18. Further mechanistic studies revealed that acidosis-induced ASIC1a activation results in the increase of BK channel currents, with the subsequent K+ efflux and a low concentration of intracellular K+, which activated NLRP1 inflammasome. Furthermore, these effects of acidosis could be blocked by specific ASIC1a inhibitor PcTX1 and BK channel inhibitor IbTX. The data also demonstrated neutralization of NLRP1-protected cortical neurons against injury induced by extracellular acidosis.

Conclusions

Our data showed that NLRP1 inflammasome could be activated by extracellular acidosis though ASIC-BK channel K+ signal pathway and was involved in extracellular acidosis-induced cortical neuronal injury.
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Literature
1.
de Rivero Vaccari JP, Dietrich WD, Keane RW. Therapeutics targeting the inflammasome after central nervous system injury. Transl Res. 2015;167(1):35–45.PubMedCrossRef
2.
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.PubMedCrossRef
3.
Minkiewicz J, de Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013;61:1113–21.PubMedCrossRef
4.
Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20:319–25.PubMedCrossRef
5.
Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A. 2010;107:3076–80.PubMedPubMedCentralCrossRef
6.
Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
8.
de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 2008;28:3404–14.PubMedCrossRef
9.
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.PubMedPubMedCentralCrossRef
10.
Pontillo A, Catamo E, Arosio B, Mari D, Crovella S. NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis Assoc Disord. 2011;26:277–81.CrossRef
11.
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.PubMedPubMedCentralCrossRef
12.
Li WW, Guo TZ, Liang D, Shi X, Wei T, Kingery WS, et al. The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain. 2009;147:277–86.PubMedCrossRef
13.
Tan CC, Zhang JG, Tan MS, Chen H, Meng DW, Jiang T, et al. NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model. J Neuroinflammation. 2015;12:18.PubMedPubMedCentralCrossRef
14.
Wang YZ, Xu TL. Acidosis, acid-sensing ion channels, and neuronal cell death. Mol Neurobiol. 2011;44:350–8.PubMedCrossRef
15.
Nedergaard M, Kraig RP, Tanabe J, Pulsinelli WA. Dynamics of interstitial and intracellular pH in evolving brain infarct. Am J Physiol. 1991;260:R581–8.PubMedPubMedCentral
16.
Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol. 2010;6:274–85.PubMedCrossRef
17.
Somjen GG. Acidification of interstitial fluid in hippocampal formation caused by seizures and by spreading depression. Brain Res. 1984;311:186–8.PubMedCrossRef
18.
Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, et al. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998;273:12817–26.PubMedCrossRef
19.
Pirchl M, Marksteiner J, Humpel C. Effects of acidosis on brain capillary endothelial cells and cholinergic neurons: relevance to vascular dementia and Alzheimer’s disease. Neurol Res. 2006;28:657–64.PubMedCrossRef
20.
Bowen BC, Block RE, Sanchez-Ramos J, Pattany PM, Lampman DA, Murdoch JB, et al. Proton MR spectroscopy of the brain in 14 patients with Parkinson disease. AJNR Am J Neuroradiol. 1995;16:61–8.PubMed
21.
Koga K, Mori A, Ohashi S, Kurihara N, Kitagawa H, Ishikawa M, et al. H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice. Eur J Neurosci. 2006;23:1077–81.PubMedCrossRef
22.
Jenkins BG, Koroshetz WJ, Beal MF, Rosen BR. Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology. 1993;43:2689–95.PubMedCrossRef
23.
Jancic CC, Cabrini M, Gabelloni ML, Rodriguez Rodrigues C, Salamone G, Trevani AS, et al. Low extracellular pH stimulates the production of IL-1beta by human monocytes. Cytokine. 2011;57:258–68.PubMedCrossRef
24.
Rajamaki K, Nordstrom T, Nurmi K, Akerman KE, Kovanen PT, Oorni K, et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 2013;288:13410–9.PubMedPubMedCentralCrossRef
25.
Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. A proton-gated cation channel involved in acid-sensing. Nature. 1997;386:173–7.PubMedCrossRef
26.
27.
Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol. 2008;8:25–32.PubMedPubMedCentralCrossRef
28.
Tong J, Wu WN, Kong X, Wu PF, Tian L, Du W, et al. Acid-sensing ion channels contribute to the effect of acidosis on the function of dendritic cells. J Immunol. 2011;186:3686–92.PubMedCrossRef
29.
Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118:687–98.PubMedCrossRef
30.
Gao J, Duan B, Wang DG, Deng XH, Zhang GY, Xu L, et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron. 2005;48:635–46.PubMedCrossRef
31.
Arias RL, Sung ML, Vasylyev D, Zhang MY, Albinson K, Kubek K, et al. Amiloride is neuroprotective in an MPTP model of Parkinson’s disease. Neurobiol Dis. 2008;31:334–41.PubMedCrossRef
32.
Wong HK, Bauer PO, Kurosawa M, Goswami A, Washizu C, Machida Y, et al. Blocking acid-sensing ion channel 1 alleviates Huntington’s disease pathology via an ubiquitin-proteasome system-dependent mechanism. Hum Mol Genet. 2008;17:3223–35.PubMedCrossRef
33.
Ziemann AE, Schnizler MK, Albert GW, Severson MA, Howard 3rd MA, Welsh MJ, et al. Seizure termination by acidosis depends on ASIC1a. Nat Neurosci. 2008;11:816–22.PubMedPubMedCentralCrossRef
34.
Fann DY, Lee SY, Manzanero S, Chunduri P, Sobey CG, Arumugam TV. Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 2013;12:941–66.PubMedCrossRef
35.
Wu WN, Wu PF, Chen XL, Zhang Z, Gu J, Yang YJ, et al. Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-sensing ion channel 1a and L-type calcium channels. Br J Pharmacol. 2011;164:1445–59.PubMedPubMedCentralCrossRef
36.
37.
Yang MJ, Wang F, Wang JH, Wu WN, Hu ZL, Cheng J, et al. PI3K integrates the effects of insulin and leptin on large-conductance Ca2+-activated K+ channels in neuropeptide Y neurons of the hypothalamic arcuate nucleus. Am J Physiol Endocrinol Metab. 2009;298:E193–201.PubMedCrossRef
38.
Wu WN, Wu PF, Zhou J, Guan XL, Zhang Z, Yang YJ, et al. Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca(2)(+)-dependent mechanism involving voltage-gated L-type calcium channel. Mol Pharmacol. 2013;84:876–87.PubMedCrossRef
39.
40.
Petroff EY, Price MP, Snitsarev V, Gong H, Korovkina V, Abboud FM, et al. Acid-sensing ion channels interact with and inhibit BK K+ channels. Proc Natl Acad Sci U S A. 2008;105:3140–4.PubMedPubMedCentralCrossRef
41.
Yermolaieva O, Leonard AS, Schnizler MK, Abboud FM, Welsh MJ. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci U S A. 2004;101:6752–7.PubMedPubMedCentralCrossRef
42.
Stelmashuk EV, Belyaeva EA, Isaev NK. Effect of acidosis, oxidative stress, and glutamate toxicity on the survival of mature and immature cultured cerebellar granule cells. Neurochemical Journal. 2007;1:66–9.CrossRef
43.
Isaev NK, Stelmashook EV, Plotnikov EY, Khryapenkova TG, Lozier ER, Doludin YV, et al. Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia. Biochemistry (Mosc). 2008;73:1171–5.CrossRef
44.
Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006;38:240–4.PubMedCrossRef
45.
Fink SL, Bergsbaken T, Cookson BT. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc Natl Acad Sci U S A. 2008;105:4312–7.PubMedPubMedCentralCrossRef
46.
Cavailles P, Sergent V, Bisanz C, Papapietro O, Colacios C, Mas M, et al. The rat Toxo1 locus directs toxoplasmosis outcome and controls parasite proliferation and spreading by macrophage-dependent mechanisms. Proc Natl Acad Sci U S A. 2006;103:744–9.PubMedPubMedCentralCrossRef
47.
Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25:713–24.PubMedCrossRef
48.
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.PubMedPubMedCentralCrossRef
49.
Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14:1583–9.PubMedCrossRef
50.
Frederick Lo C, Ning X, Gonzales C, Ozenberger BA. Induced expression of death domain genes NALP1 and NALP5 following neuronal injury. Biochem Biophys Res Commun. 2008;366:664–9.PubMedCrossRef
51.
Silverman WR, de Rivero Vaccari JP, Locovei S, Qiu F, Carlsson SK, Scemes E, et al. The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem. 2009;284:18143–51.PubMedPubMedCentralCrossRef
52.
53.
Wang Y, Chang Z. Heat-shock response down-regulates interleukin-18 expression in murine peritoneal macrophages. Biol Cell. 2005;97:551–6.PubMedCrossRef
54.
Petroff E, Snitsarev V, Gong H, Abboud FM. Acid sensing ion channels regulate neuronal excitability by inhibiting BK potassium channels. Biochem Biophys Res Commun. 2012;426:511–5.PubMedPubMedCentralCrossRef
55.
Isaev NK, Stelmashook EV, Lukin SV, Freyer D, Mergenthaler P, Zorov DB. Acidosis-induced zinc-dependent death of cultured cerebellar granule neurons. Cell Mol Neurobiol. 2010;30:877–83.PubMedCrossRef
Metadata
Title
Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons
Authors
Yu-Chan Wang
Wei-Zu Li
Yu Wu
Yan-Yan Yin
Liu-Yi Dong
Zhi-Wu Chen
Wen-Ning Wu
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0465-7

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