Dim light at night shifts microglia to a pro-inflammatory state after cerebral ischemia, altering stroke outcome in mice

Jennifer A Liu; William H Walker 2nd; O Hecmarie Meléndez-Fernández; Jacob R Bumgarner; Ning Zhang; James C Walton; Gordon P Meares; A Courtney DeVries; Randy J Nelson

doi:10.1016/j.expneurol.2024.114796

Dim light at night shifts microglia to a pro-inflammatory state after cerebral ischemia, altering stroke outcome in mice

Exp Neurol. 2024 Apr 25:377:114796. doi: 10.1016/j.expneurol.2024.114796. Online ahead of print.

Authors

Jennifer A Liu¹, William H Walker 2nd², O Hecmarie Meléndez-Fernández², Jacob R Bumgarner², Ning Zhang², James C Walton², Gordon P Meares³, A Courtney DeVries⁴, Randy J Nelson²

Affiliations

¹ Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States. Electronic address: jliu324@jhu.edu.
² Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States.
³ Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States; Department of Microbiology, Immunology, & Cell Biology, West Virginia University, Morgantown, WV, United States.
⁴ Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, United States; Department of Medicine, West Virginia University, Morgantown, WV, United States; West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, United States.

PMID: 38677449
DOI: 10.1016/j.expneurol.2024.114796

Abstract

Circadian rhythms are endogenous biological cycles that regulate physiology and behavior and are set to precisely 24-h by light exposure. Light at night (LAN) dysregulates physiology and function including immune response; a critical component that contributes to stroke pathophysiological progression of neuronal injury and may impair recovery from injury. The goal of this study is to explore the effects of dim LAN (dLAN) in a murine model of ischemic stroke to assess how nighttime lighting from hospital settings can affect stroke outcome. Further, this study sought to identify mechanisms underlying pathophysiological changes to immune response after circadian disruption. Male and female adult Swiss Webster (CFW) mice were subjected to transient or permanent focal cerebral ischemia, then were subsequently placed into either dark night conditions (LD) or one night of dLAN (5 lx). 24 h post-stroke, sensorimotor impairments and infarct sizes were quantified. A single night of dLAN following MCAO increased infarct size and sensorimotor deficits across both sexes and reduced survival in males after 24 h. Flow cytometry was performed to assess microglial phenotypes after MCAO, and revealed that dLAN altered the percentage of microglia that express pro-inflammatory markers (MHC II+ and IL-6) and microglia that express CD206 and IL-10 that likely contributed to poor ischemic outcomes. Following these results, microglia were reduced in the brain using Plexxikon 5622 (PLX 5622) a CSFR1 inhibitor, then the mice received an MCAO and were exposed to LD or dLAN conditions for 24 h. Microglial depletion by PLX5622 resulted in infarct sizes that were comparable between lighting conditions. This study provides supporting evidence that environmental lighting exacerbates ischemic injury and post-stroke mortality by a biological mechanism that exposure to dLAN causes a fundamental shift of activated microglial phenotypes from beneficial to detrimental at an early time point after stroke, resulting in irreversible neuronal death.

Keywords: Animal model; Circadian disruption; Circadian rhythms; Ischemia; Light at night; Microglia; Microglial activation; Proinflammatory cytokines; Stroke.