Elevated intracranial pressure induces IL‑1β and IL‑18 overproduction via activation of the NLRP3 inflammasome in microglia of ischemic adult rats

Ding,Hongguang; Li,Ya; Wen,Miaoyun; Liu,Xinqiang; Han,Yongli; Zeng,Hongke

doi:10.3892/ijmm.2020.4779

Elevated intracranial pressure induces IL‑1β and IL‑18 overproduction via activation of the NLRP3 inflammasome in microglia of ischemic adult rats

Authors:
- Hongguang Ding
- Ya Li
- Miaoyun Wen
- Xinqiang Liu
- Yongli Han
- Hongke Zeng
View Affiliations

Affiliations: Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
Published online on: November 3, 2020 https://doi.org/10.3892/ijmm.2020.4779
Pages: 183-194
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Elevated intracranial pressure (ICP) is one of the most common complications following an ischemic stroke, and has implications for the clinical and neurological outcomes. The aim of the present study was to examine whether elevated ICP may increase IL‑1β and IL‑18 secretion by activating the NOD‑like receptor protein 3 (NLRP3) inflammasome in microglia of ischemic adult rats. Sprague‑Dawley rats that underwent middle cerebral artery occlusion were used for assessment of ICP. Reactive oxygen species (ROS) production was detected, and western blotting and immunofluorescence staining were used to determine the expression levels of Caspase‑1, gasdermin D‑N domains (GSDMD‑N), IL‑1β and IL‑18 in microglial cells. ICP levels were significantly increased, which was accompanied by ROS overproduction, in the brain tissue following ischemia‑reperfusion (IR) injury in rats. Treatment with 10% hypertonic saline by intravenous injection significantly reduced the ICP and ROS levels of the rats. Furthermore, high pressure (20 mmHg) combined with oxygen‑glucose deprivation (OGD) treatment resulted in increased ROS production in BV‑2 microglial cells compared with those subjected to OGD treatment alone in vitro. Elevated pressure upregulated the expression of Caspase‑1, GSDMD‑N, IL‑18 and IL‑1β in IR‑treated or OGD‑treated microglia both in vivo and in vitro. More importantly, Caspase‑1, GSDMD‑N, IL‑18 and IL‑1β expression in microglia was significantly downregulated when elevated pressure was reduced or removed. These results suggested that elevated ICP‑induced IL‑1β and IL‑18 overproduction via activation of the NLRP3 inflammasome by ischemia‑activated microglia may augment neuroinflammation.

View Figures

View References

1	Phipps MS and Cronin CA: Management of acute ischemic stroke. BMJ. 368:169832020.
2	Khandelwal P, Yavagal DR and Sacco RL: Acute ischemic stroke intervention. J Am Coll Cardiol. 67:2631–2644. 2016. View Article : Google Scholar : PubMed/NCBI
3	Blaha M, Schwab J, Vajnerova O, Bednar M, Vajner L and Michal T: Intracranial pressure and experimental model of diffuse brain injury in rats. J Korean Neurosurg Soc. 47:7–10. 2010. View Article : Google Scholar : PubMed/NCBI
4	Caltagirone C, Cisari C, Schievano C, Di Paola R, Cordaro M, Bruschetta G, Esposito E and Cuzzocrea S: Coultramicronized palmitoylethanolamide/luteolin in the treatment of cerebral ischemia: From rodent to man. Transl Stroke Res. 7:54–69. 2016. View Article : Google Scholar
5	Robinson JD: Management of refractory intracranial pressure. Crit Care Nurs Clin North Am. 28:67–75. 2016. View Article : Google Scholar : PubMed/NCBI
6	Shah A, Almenawer S and Hawryluk G: Timing of decompressive craniectomy for ischemic stroke and traumatic brain injury: A review. Front Neurol. 10:112019. View Article : Google Scholar : PubMed/NCBI
7	Wei CC, Zhang ST, Tan G, Zhang SH and Liu M: Impact of anemia on in-hospital complications after ischemic stroke. Eur J Neurol. 25:768–774. 2018. View Article : Google Scholar : PubMed/NCBI
8	Jin R, Yang G and Li G: Inflammatory mechanisms in ischemic stroke: Role of inflammatory cells. J Leukoc Biol. 87:779–789. 2010. View Article : Google Scholar : PubMed/NCBI
9	Zhao SC, Ma LS, Chu ZH, Xu H, Wu WQ and Liu F: Regulation of microglial activation in stroke. Acta Pharmacol Sin. 38:445–458. 2017. View Article : Google Scholar : PubMed/NCBI
10	Wang S, Zhang H and Xu Y: Crosstalk between microglia and T cells contributes to brain damage and recovery after ischemic stroke. Neurol Res. 38:495–503. 2016. View Article : Google Scholar : PubMed/NCBI
11	Zhao TZ, Ding Q, Hu J, He SM, Shi F and Ma LT: GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain Behav. 6:e4492016. View Article : Google Scholar
12	Ma Y, Wang J, Wang Y and Yang GY: The biphasic function of microglia in ischemic stroke. Prog Neurobiol. 157:247–272. 2017. View Article : Google Scholar
13	Goldmann T, Tay TL and Prinz M: Love and death: Microglia, NLRP3 and the Alzheimer's brain. Cell Res. 23:595–596. 2013. View Article : Google Scholar : PubMed/NCBI
14	Cho MH, Cho K, Kang HJ, Jeon EY, Kim HS, Kwon HJ, Kim HM, Kim DH and Yoon SY: Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy. 10:1761–1775. 2014. View Article : Google Scholar : PubMed/NCBI
15	Houtman J, Freitag K, Gimber N, Schmoranzer J, Heppner FL and Jendrach M: Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. Embo J. 38:e994302019. View Article : Google Scholar : PubMed/NCBI
16	Panicker N, Sarkar S, Harischandra DS, Neal M, Kam TI, Jin H, Saminathan H, Langley M, Charli A, Samidurai M, et al: Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J Exp Med. 216:1411–1430. 2019. View Article : Google Scholar : PubMed/NCBI
17	Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, Zhou ML, Zhu L and Hang CH: Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 38:2072–2083. 2013. View Article : Google Scholar : PubMed/NCBI
18	Zhang N, Zhang X, Liu X, Wang H, Xue J, Yu J, Kang N and Wang X: Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice. Mediators Inflamm. 2014:3705302014. View Article : Google Scholar : PubMed/NCBI
19	Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, Tardivel A, Heuschling P and Dostert C: NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 10:e1306242015. View Article : Google Scholar
20	Xu X, Zhang L, Ye X, Hao Q, Zhang T, Cui G and Yu M: Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflamma-some activation in BV2 cells after cerebral ischemia reperfusion. Inflamm Res. 67:57–65. 2018. View Article : Google Scholar
21	Wang H, Zhong D, Chen H, Jin J, Liu Q and Li G: NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice. Life Sci. 227:101–113. 2019. View Article : Google Scholar : PubMed/NCBI
22	Kelley N, Jeltema D, Duan Y and He Y: The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 20:33282019. View Article : Google Scholar :
23	Harijith A, Ebenezer DL and Natarajan V: Reactive oxygen species at the crossroads of inflammasome and inflammation. Front Physiol. 5:3522014. View Article : Google Scholar : PubMed/NCBI
24	Fann DY, Lee SY, Manzanero S, Chunduri P, Sobey CG and Arumugam TV: Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 12:941–966. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q and Yi F: NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 34:660–667. 2014. View Article : Google Scholar : PubMed/NCBI
26	Huang LQ, Zhu GF, Deng YY, Jiang WQ, Fang M, Chen CB, Cao W, Wen MY, Han YL and Zeng HK: Hypertonic saline alleviates cerebral edema by inhibiting microglia-derived TNF-α and IL-1β-induced Na-K-Cl Cotransporter up-regulation. J Neuroinflammation. 11:1022014. View Article : Google Scholar
27	Ding HG, Deng YY, Yang RQ, Wang QS, Jiang WQ, Han YL, Huang LQ, Wen MY, Zhong WH, Li XS, et al: Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: Implication in cognitive impairment in hypoxemic adult rats. J Neuroinflammation. 15:42018. View Article : Google Scholar
28	Changa AR, Czeisler BM and Lord AS: Management of elevated intracranial pressure: A review. Curr Neurol Neurosci Rep. 19:992019. View Article : Google Scholar : PubMed/NCBI
29	Fernando SM, Tran A, Cheng W, Rochwerg B, Taljaard M, Kyeremanteng K, English SW, Sekhon MS, Griesdale D, Dowlatshahi D, et al: Diagnosis of elevated intracranial pressure in critically ill adults: Systematic review and meta-analysis. BMJ. 366:l42252019. View Article : Google Scholar : PubMed/NCBI
30	Wu AG, Samadani U, Slusher TM, Zhang L and Kiragu AW: 23.4% hypertonic saline and intracranial pressure in severe traumatic brain injury among children: A 10-year retrospective analysis. Pediatr Crit Care Med. 20:466–473. 2019. View Article : Google Scholar : PubMed/NCBI
31	Pasarikovski CR, Alotaibi NM, Al-Mufti F and Macdonald RL: Hypertonic saline for increased intracranial pressure after aneurysmal subarachnoid hemorrhage: A systematic review. World Neurosurg. 105:1–6. 2017. View Article : Google Scholar : PubMed/NCBI
32	Strapazzon G, Malacrida S, Vezzoli A, Dal Cappello T, Falla M, Lochner P, Moretti S, Procter E, Brugger H and Mrakic-Sposta S: Oxidative stress response to acute hypobaric hypoxia and its association with indirect measurement of increased intracranial pressure: A field study. Sci Rep. 6:324262016. View Article : Google Scholar : PubMed/NCBI
33	Abdullah Z, Rakkar K, Bath PM and Bayraktutan U: Inhibition of TNF-α protects in vitro brain barrier from ischaemic damage. Mol Cell Neurosci. 69:65–79. 2015. View Article : Google Scholar : PubMed/NCBI
34	Wong R, Lénárt N, Hill L, Toms L, Coutts G, Martinecz B, Császár E, Nyiri G, Papaemmanouil A, Waisman A, et al: Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. Brain Behav Immun. 76:126–138. 2019. View Article : Google Scholar :
35	Kho DT, Johnson R, Robilliard L, du Mez E, McIntosh J, O'Carroll SJ, Angel CE and Graham ES: ECIS technology reveals that monocytes isolated by CD14+ve selection mediate greater loss of BBB integrity than untouched monocytes, which occurs to a greater extent with IL-1β activated endothelium in comparison to TNFα. PLoS One. 12:e1802672017. View Article : Google Scholar
36	Liang JM, Xu HY, Zhang XJ, Li X, Zhang HB and Ge PF: Role of mitochondrial function in the protective effects of ischaemic postconditioning on ischaemia/reperfusion cerebral damage. J Int Med Res. 41:618–627. 2013. View Article : Google Scholar : PubMed/NCBI
37	Li H, Feng J, Zhang Y, Feng J, Wang Q, Zhao S, Meng P and Li J: Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway. Redox Biol. 20:261–274. 2019. View Article : Google Scholar
38	Deretic V and Levine B: Autophagy balances inflammation in innate immunity. Autophagy. 14:243–251. 2018. View Article : Google Scholar :
39	Heneka MT, McManus RM and Latz E: Inflammasome signal-ling in brain function and neurodegenerative disease. Nat Rev Neurosci. 19:610–621. 2018. View Article : Google Scholar : PubMed/NCBI