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

TLDR

Cortical spreading depolarization (CSD) triggers pro‑inflammatory gene expression, yet previous work relied on invasive methods that themselves provoke inflammation. The study sought to eliminate injury confounders by inducing CSDs non‑invasively through optogenetics in Thy1‑ChR2 transgenic mice. CSDs were induced non‑invasively via optogenetic stimulation of the intact skull and corroborated by minimally invasive KCl application through a thinned skull. Six non‑invasive CSDs rapidly elevated IL‑1β, CCL2, and TNF‑α mRNA (peaking at 1, 2, and 4 h), with a single CSD producing an ultra‑early IL‑1β surge within 10 min; IL‑6 and ICAM‑1 rose modestly, the response was attenuated in IL‑1R1 knockout mice and suppressed by dexamethasone but not ibuprofen, and systemic inflammation remained unchanged, marking the first report of pro‑inflammatory gene expression after non‑invasive CSDs and implicating a role in migraine and acute brain injury.

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.