PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats

Flores, Jerry; Klebe, Damon; Rolland, William; Lekic, Tim; Krafft, Paul R.; Zhang, Junyi

doi:10.1016/j.nbd.2015.12.015

Cited by 78 publications

(88 citation statements)

References 59 publications

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“…Clinical evidence shows that hematoma size and expansion are the major determinants of ICH outcomes (Brott et al, 1997; LoPresti et al, 2014). Until now, however, little preclinical work has evaluated potential strategies to limit hematoma expansion or accelerate hematoma resolution after ICH (Flores et al, 2016; King et al, 2011; Wu et al, 2016; Zhao et al, 2015b; Zhao et al, 2007b). …”

Section: Introductionmentioning

confidence: 99%

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Chang

Wan

et al. 2017

Neurobiology of Disease

113

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Microglia/macrophages (MMΦ) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMΦ polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMΦ dynamics after ICH in mice and evaluated the relevance of MMΦ polarity to hematoma resolution. MMΦ accumulated within the hematoma territory until at least 14 days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1–1.5 h after ICH and specifically presented a “protective” alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMΦ classic activation dominated at the chronic stage of ICH. We enhanced MMΦ alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMΦ alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMΦ respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMΦ aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMΦ phagocytosis and hematoma clearance in ICH.

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Section: Introductionmentioning

confidence: 99%

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Chang

Wan

et al. 2017

Neurobiology of Disease

113

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“…The membrane was then exposed to radiography films to display the protein bands. Lastly, the density of bands was analyzed for the relative density of the resultant protein immunoblot by ImageJ software (NIH) …”

Section: Methodsmentioning

confidence: 99%

Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

et al. 2019

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Aims Reactive astrogliosis plays a critical role in neurological deficits after germinal matrix hemorrhage (GMH). It has been reported that interleukin‐17A and IL‐17A receptor IL‐17RA/(C/EBPβ)/SIRT1 signaling pathway enhances reactive astrogliosis after brain injuries. We evaluated the effects of secukinumab on reactive astrogliosis in a rat pup model of GMH. Methods A total of 146 Sprague Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of collagenase. Secukinumab was administered intranasally 1 hour post‐GMH. C/EBPβ CRISPR or SIRT1 antagonist EX527 was administrated intracerebroventricularly (icv) 48 hours and 1 hour before GMH induction, respectively. Neurobehavior, Western blot, histology, and immunohistochemistry were used to assess treatment regiments in the short term and long term. Results The endogenous IL‐17A, IL‐17RA, C/EBPβ, and GFAP and proliferation marker CyclinD1 were increased, while SIRT1 expression was decreased after GMH. Secukinumab treatment improved neurological deficits, reduced ventriculomegaly, and increased cortical thickness. Additionally, treatment increased SIRT1 expression and lowered proliferation proteins PCNA and CyclinD1 as well as GFAP expression. C/EBPβ CRISPR activation plasmid and EX527 reversed the antireactive astrogliosis effects of secukinumab. Conclusion Secukinumab attenuated reactive astrogliosis and reduced neurological deficits after GMH, partly by regulating IL‐17RA/(C/EBPβ)/SIRT1 pathways. Secukinumab may provide a promising therapeutic strategy for GMH patients.

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“…bexarotene solution (5 mg/kg) or an equal volume of vehicle or bexarotene solution (5 mg/kg) + GW9662 solution (4 mg/kg) was administered intraperitoneally 1 h after ICH for the rst time, followed by daily injections until sacri ce. The dosage and time points of bexarotene and GW9662 were based on a previous study [21,22].…”

Section: Drug Administrationmentioning

confidence: 99%

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

Chen

Zhou

et al. 2020

Preprint

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Background: Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH.Methods: ICH mouse models were established by the stereotactic injection of autologous arterial blood into the right basal ganglia. The selective RXR-α agonist bexarotene and peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist GW9662 were administered intraperitoneally at 1 h after ICH. Post-ICH assessments were in the form of magnetic resonance imaging scans, neurological tests, Western blotting, enzyme-linked immunosorbent assays, and immunofluorescence. Results: Pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in the microglia/macrophages, neurons, and astrocytes. Mechanically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, alongside reducing neuroinflammation by modulating microglia/macrophages reprograming into the M2 phenotype from M1 phenotype. However, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662.Conclusion: The pharmacological activation of RXR-α conferred robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.

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PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats

Cited by 78 publications

References 59 publications

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Secukinumab attenuates reactive astrogliosis via IL‐17RA/(C/EBPβ)/SIRT1 pathway in a rat model of germinal matrix hemorrhage

Pharmacological Activation of RXR-α Promotes Hematoma Absorption in a PPAR-γ-Dependent Pathway After Intracerebral Hemorrhage

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