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Updated: Nov 10, 2025
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Published on: June 20, 2025
Involvement of the Microglial Aryl Hydrocarbon Receptor in Neuroinflammation and Vasogenic Edema after Ischemic
Miki Tanaka1, Masaho Fujikawa1, Ami Oguro1
1Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan.
Abstract:
Microglia are activated after ischemic stroke and induce neuroinflammation. The expression of the aryl hydrocarbon receptor (AhR) has recently been reported to elicit cytokine expression. We previously reported that microglial activation mediates ischemic edema progression. Thus, the purpose of this study was to examine the role of AhR in inflammation and edema after ischemia using a mouse middle cerebral artery occlusion (MCAO) model. MCAO upregulated AhR expression in microglia during ischemia. MCAO increased the expression of tumor necrosis factor α (TNFα) and then induced edema progression, and worsened the modified neurological severity scores, with these being suppressed by administration of an AhR antagonist, CH223191. In THP-1 macrophages, the NADPH oxidase (NOX) subunit p47phox was significantly increased by AhR ligands, especially under inflammatory conditions. Suppression of NOX activity by apocynin or elimination of superoxide by superoxide dismutase decreased TNFα expression, which was induced by the AhR ligand. AhR ligands also elicited p47phox expression in mouse primary microglia. Thus, p47phox may be important in oxidative stress and subsequent inflammation. In MCAO model mice, P47phox expression was upregulated in microglia by ischemia. Lipid peroxidation induced by MCAO was suppressed by CH223191. Taken together, these findings suggest that AhR in the microglia is involved in neuroinflammation and subsequent edema, after MCAO via p47phox expression upregulation and oxidative stress.
Insights
The aryl hydrocarbon receptor (AhR) in microglia drives neuroinflammation and edema after ischemic stroke. Blocking AhR reduces inflammation and brain swelling, suggesting a therapeutic target for stroke recovery.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia activation causes neuroinflammation post-ischemic stroke.
- Aryl hydrocarbon receptor (AhR) expression is linked to cytokine production.
- Microglial activation contributes to ischemic edema progression.
Purpose of the Study:
- To investigate the role of AhR in neuroinflammation and edema following ischemic stroke.
- To analyze AhR's involvement in the middle cerebral artery occlusion (MCAO) mouse model.
Main Methods:
- Utilized a mouse MCAO model to induce ischemia.
- Administered an AhR antagonist (CH223191) to assess its effects.
- Examined NADPH oxidase (NOX) subunit p47phox expression in macrophages and microglia.
- Measured TNFα expression, oxidative stress markers, and lipid peroxidation.
Main Results:
- MCAO upregulated AhR expression in microglia and increased TNFα, leading to edema and worsened neurological scores.
- AhR antagonist CH223191 suppressed these MCAO-induced effects.
- AhR ligands increased p47phox expression in macrophages and microglia, linked to oxidative stress and TNFα production.
- CH223191 treatment reduced MCAO-induced lipid peroxidation.
Conclusions:
- Microglial AhR signaling contributes to ischemic stroke-induced neuroinflammation and edema.
- AhR activation upregulates p47phox, promoting oxidative stress and subsequent inflammation.
- Targeting microglial AhR may offer a novel therapeutic strategy for ischemic stroke.
