Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex

Tsubasa Takizawa, Tao Qin, Andreia Lopes de Morais, Kazutaka Sugimoto, Joon Yong Chung, Liza Morsett, Inge Mulder, Paul Fischer, Tomoaki Suzuki, Maryam Anzabi, Maximilian Böhm, Wen Sheng Qu, Takeshi Yanagisawa, Suzanne Hickman, Joseph El Khoury, Michael J. Whalen, Andrea M. Harriott, David Y. Chung, Cenk Ayata

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
Publication statusPublished - 2019 Jan 1
Externally publishedYes

Fingerprint

Interleukin-1
Cerebral Cortex
Skull
Tumor Necrosis Factor-alpha
Optogenetics
Inflammation
Gene Expression
Interleukin-1 Receptors
Chemokine CCL2
Ibuprofen
Intercellular Adhesion Molecule-1
Migraine Disorders
Knockout Mice
Brain Injuries
Dexamethasone
Transgenic Mice
Interleukin-6
Ligands
Messenger RNA
Wounds and Injuries

Keywords

  • Cortical spreading depolarization
  • dexamethasone
  • inflammation
  • NSAIDs
  • optogenetics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex. / Takizawa, Tsubasa; Qin, Tao; Lopes de Morais, Andreia; Sugimoto, Kazutaka; Chung, Joon Yong; Morsett, Liza; Mulder, Inge; Fischer, Paul; Suzuki, Tomoaki; Anzabi, Maryam; Böhm, Maximilian; Qu, Wen Sheng; Yanagisawa, Takeshi; Hickman, Suzanne; Khoury, Joseph El; Whalen, Michael J.; Harriott, Andrea M.; Chung, David Y.; Ayata, Cenk.

In: Journal of Cerebral Blood Flow and Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

Takizawa, T, Qin, T, Lopes de Morais, A, Sugimoto, K, Chung, JY, Morsett, L, Mulder, I, Fischer, P, Suzuki, T, Anzabi, M, Böhm, M, Qu, WS, Yanagisawa, T, Hickman, S, Khoury, JE, Whalen, MJ, Harriott, AM, Chung, DY & Ayata, C 2019, 'Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex', Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678X19859381
Takizawa, Tsubasa ; Qin, Tao ; Lopes de Morais, Andreia ; Sugimoto, Kazutaka ; Chung, Joon Yong ; Morsett, Liza ; Mulder, Inge ; Fischer, Paul ; Suzuki, Tomoaki ; Anzabi, Maryam ; Böhm, Maximilian ; Qu, Wen Sheng ; Yanagisawa, Takeshi ; Hickman, Suzanne ; Khoury, Joseph El ; Whalen, Michael J. ; Harriott, Andrea M. ; Chung, David Y. ; Ayata, Cenk. / Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex. In: Journal of Cerebral Blood Flow and Metabolism. 2019.
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abstract = "Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1β, CCL2, and TNF-α, and revealed an ultra-early IL-1β response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1β as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.",
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AU - Sugimoto, Kazutaka

AU - Chung, Joon Yong

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AU - Anzabi, Maryam

AU - Böhm, Maximilian

AU - Qu, Wen Sheng

AU - Yanagisawa, Takeshi

AU - Hickman, Suzanne

AU - Khoury, Joseph El

AU - Whalen, Michael J.

AU - Harriott, Andrea M.

AU - Chung, David Y.

AU - Ayata, Cenk

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