Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization
Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains...
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| Format: | Article |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.719823/full |
| _version_ | 1819146001431134208 |
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| author | Qian Jiang Ding Wei Xuejun He Chao Gan Xiaobing Long Huaqiu Zhang |
| author_facet | Qian Jiang Ding Wei Xuejun He Chao Gan Xiaobing Long Huaqiu Zhang |
| author_sort | Qian Jiang |
| collection | DOAJ |
| description | Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown.Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator–activated receptor-gamma (PPARγ) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ), microglial phenotypic markers (iNOS, COX2, and CD86 for “M1” polarization; Arg1, Ym1, and CD206 for “M2” polarization), PPARγ, and NF-κB were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence.Results: Phi markedly restrained the pro-inflammatory (“M1” state) cytokines and promoted anti-inflammatory (“M2” polarization) cytokines in LPS-mediated microglia. Phi mitigated “M1” polarization and promoted “M2” polarization of microglia via enhancing PPARγ and inhibiting the NF-κB pathway. The PPARγ antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted “M2” polarization, whereas it repressed the “M1” polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment.Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPARγ/NF-κB pathway, which provides a potential therapeutic drug against TBI. |
| first_indexed | 2024-12-22T13:06:59Z |
| format | Article |
| id | doaj.art-b5bfe24e4d99429390dae40be0ad25de |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T13:06:59Z |
| publishDate | 2021-10-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-b5bfe24e4d99429390dae40be0ad25de2022-12-21T18:24:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-10-011210.3389/fphar.2021.719823719823Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial PolarizationQian Jiang0Ding Wei1Xuejun He2Chao Gan3Xiaobing Long4Huaqiu Zhang5Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurosurgery, Tianyou Hospital Affiliated to Wuhan University of Science & Technology, Wuhan, ChinaDepartment of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Emergency, Renmin Hospital of Wuhan University, Wuhan, ChinaDepartment of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaBackground: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown.Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator–activated receptor-gamma (PPARγ) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ), microglial phenotypic markers (iNOS, COX2, and CD86 for “M1” polarization; Arg1, Ym1, and CD206 for “M2” polarization), PPARγ, and NF-κB were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence.Results: Phi markedly restrained the pro-inflammatory (“M1” state) cytokines and promoted anti-inflammatory (“M2” polarization) cytokines in LPS-mediated microglia. Phi mitigated “M1” polarization and promoted “M2” polarization of microglia via enhancing PPARγ and inhibiting the NF-κB pathway. The PPARγ antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted “M2” polarization, whereas it repressed the “M1” polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment.Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPARγ/NF-κB pathway, which provides a potential therapeutic drug against TBI.https://www.frontiersin.org/articles/10.3389/fphar.2021.719823/fulltraumatic brain injuryphillyrinmicrogliaPPARγneuroinflammationblood–brain barrier |
| spellingShingle | Qian Jiang Ding Wei Xuejun He Chao Gan Xiaobing Long Huaqiu Zhang Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization Frontiers in Pharmacology traumatic brain injury phillyrin microglia PPARγ neuroinflammation blood–brain barrier |
| title | Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization |
| title_full | Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization |
| title_fullStr | Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization |
| title_full_unstemmed | Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization |
| title_short | Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization |
| title_sort | phillyrin prevents neuroinflammation induced blood brain barrier damage following traumatic brain injury via altering microglial polarization |
| topic | traumatic brain injury phillyrin microglia PPARγ neuroinflammation blood–brain barrier |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.719823/full |
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