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Updated: Feb 19, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3
Chuan Qin1, Wen-Hui Fan1, Qian Liu1
1From the Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.Q., W.-H.F., Q.L., K.S., W.W., D.-S.T.); Department of Neurology, General Hospital of the Yangtze River Shipping, Wuhan, China (W.-H.F.); Department of Neurology, Mayo Clinic, Rochester, MN (M.M., L.-J.W.); and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (M.M., L.-J.W.).
Background And Purpose:
White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.
Methods:
Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.
Results:
Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.
Conclusions:
Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.
Insights
Fingolimod (FTY720) reduces cognitive decline and white matter damage in a chronic cerebral hypoperfusion model. It works by shifting microglia from an inflammatory M1 state to a reparative M2 state, potentially mediated by STAT3 signaling.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- White matter (WM) ischemic injury is a key feature of cerebral small vessel diseases, leading to vascular cognitive impairment.
- Microglial activation and demyelination are common in WM ischemic damage.
- Fingolimod (FTY720) is an approved immunosuppressant for multiple sclerosis.
Purpose of the Study:
- To evaluate the neuroprotective effects of Fingolimod (FTY720) in a white matter ischemia model.
- To investigate FTY720's impact on cognitive function and white matter integrity.
- To explore the underlying mechanisms of FTY720's action on microglial polarization.
Main Methods:
- A chronic white matter ischemic injury model was induced using bilateral carotid artery stenosis.
- Cognitive function was assessed using the radial maze test.
- White matter integrity, microglial activation, and STAT3 signaling were analyzed using histological and molecular techniques.
Main Results:
- Bilateral carotid artery stenosis induced cognitive decline and white matter demyelination.
- FTY720 treatment ameliorated cognitive deficits and preserved white matter integrity.
- FTY720 shifted microglia from the pro-inflammatory M1 phenotype to the M2 phenotype, promoting oligodendrogenesis.
- FTY720's effect on M2 polarization was partially dependent on STAT3 signaling.
Conclusions:
- FTY720 demonstrates neuroprotective potential against white matter ischemia and cognitive impairment.
- FTY720 exerts its effects by modulating neuroinflammation through microglial polarization.
- FTY720 may be a promising therapeutic agent for conditions involving chronic cerebral hypoperfusion and brain inflammation.
