MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGβ5/PI3K/CXCL12 signaling

Wang, Jikai; Wang, Yiping; Zuo, Yuchun; Duan, Jiajia; Pan, Aihua; Li, Jianming; Yan, Xiao‐Xin; Liu, Fei

doi:10.1007/s00221-021-06111-x

Cited by 15 publications

(15 citation statements)

References 52 publications

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“…We therefore propose that EV-associated MFG-E8 may interact with P2X4R in human microglia. This statement is further supported by our finding that cilengitide, which is a cyclized RGDcontaining pentapeptide that selectively blocks activation of the αvβ 3 and αvβ 5 integrins and is effectively used as inhibitor of MFG-E8 signaling [30,31], suppressed EV-induced migration of microglia (Figure 7). P2X4R signaling is important for phagocytosis during EAE [15].…”

Section: Discussionsupporting

confidence: 69%

“…MFG-E8 protein interacts with target cells through α V β 3 and α V β 5 integrins [27]. Cilengitide selectively blocks activation of the α V β 3 and α V β 5 integrins and is effectively used as an inhibitor of MFG-E8 signaling [30,31]. We therefore tested the effects of cilengitide on EV-induced migration of microglia.…”

Section: Inhibition Of Mfg-e8 Receptor With Cilengitide Suppressed Ev-induced Migration and Formation Of Lipid Rafts In Microgliamentioning

confidence: 99%

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Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Jonavičė

Romenskaja

Kriaučiūnaitė

et al. 2021

IJMS

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Extracellular vesicles (EVs) effectively suppress neuroinflammation and induce neuroprotective effects in different disease models. However, the mechanisms by which EVs regulate the neuroinflammatory response of microglia remains largely unexplored. Here, we addressed this issue by testing the action of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on immortalized human microglial cells. We found that EVs induced a rapid increase in intracellular Ca2+ and promoted significant ATP release in microglial cells after 20 min of treatment. Boyden chamber assays revealed that EVs promoted microglial migration by 20%. Pharmacological inhibition of different subtypes of purinergic receptors demonstrated that EVs activated microglial migration preferentially through the P2X4 receptor (P2X4R) pathway. Proximity ligation and co-immunoprecipitation assays revealed that EVs promote association between milk fat globule-epidermal growth factor-factor VIII (MFG-E8) and P2X4R proteins. Furthermore, pharmacological inhibition of αVβ3/αVβ5 integrin suppressed EV-induced cell migration and formation of lipid rafts in microglia. These results demonstrate that EVs promote microglial motility through P2X4R/MFG-E8-dependent mechanisms. Our findings provide novel insights into the molecular mechanisms through which EVs target human microglia that may be exploited for the development of new therapeutic strategies targeting disease-associated neuroinflammation.

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Section: Discussionsupporting

confidence: 69%

Section: Inhibition Of Mfg-e8 Receptor With Cilengitide Suppressed Ev-induced Migration and Formation Of Lipid Rafts In Microgliamentioning

confidence: 99%

Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Jonavičė

Romenskaja

Kriaučiūnaitė

et al. 2021

IJMS

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“…Three different doses of irisin were tested (80 μg/kg, 250 μg/kg, and 750 μg/kg) and were administered intranasally at 30 min after ICH induction [ 35 ]. Cilengitide trifluoroacetate (10 mg/kg, Selleck, USA), a selective inhibitor of αVβ3 and αVβ5 integrins, was dissolved in DMSO and administered intraperitoneally at 2 h before ICH induction [ 36 ]. Dorsomorphin (5 μg/mouse, Sigma, MO), a selective AMPK inhibitor, was dissolved in DMSO and administered intracerebroventricularly (i.c.v.)…”

Section: Methodsmentioning

confidence: 99%

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice

Wang

Tian

Tan

et al. 2022

J Neuroinflammation

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Background Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVβ5/AMPK pathway after ICH. Methods Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVβ5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function. Results Endogenous irisin and its receptor, integrin αVβ5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVβ5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVβ5, p-AMPK and Bcl-2, and decreased the expression of IL-1β, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVβ5 inhibitor cilengitide and AMPK inhibitor dorsomorphin. Conclusions This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVβ5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.

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“…Zhang et al, 2014), but is also expressed in microglia (Fuller & Van Eldik, 2008), neurovasculature (J. Wang et al, 2021), and neural progenitor cells (Brousse et al, 2021). Mfge8 is secreted by glial cells in response to apoptosis, injury, and inflammation, and binds to the damaged cells as a signal to microglia to engulf them (Fuller & Van Eldik, 2008;Yi, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Mfge8 is particularly expressed in astrocytes in the hippocampus (Cahoy et al, 2008; Saunders et al, 2018; Zeisel et al, 2018; Y. Zhang et al, 2014), but is also expressed in microglia (Fuller & Van Eldik, 2008), neurovasculature (J. Wang et al, 2021), and neural progenitor cells (Brousse et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

Hebda-Bauer

Hagenauer

Blandino

et al. 2022

Preprint

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In humans, differences in temperament are highly predictive of classes of psychopathology classified as externalizing versus internalizing disorders. To better understand the genetic and neural causes of temperamental differences, we have selectively bred two lines of rats based on their exploration of a novel environment. The bred High Responder (bHR) and bred Low Responder (bLR) rats show contrasting heritable behaviors that map onto human temperamental differences and are associated with two paths to drug abuse—sensation seeking and reactivity to psychosocial stress. To elucidate the genes that underlie the divergent behavior of bHR/bLR rats, we created a bHRxbLR F0-F1-F2 cross and performed behavioral testing, transcriptional profiling, and genetic sequencing. We used RNA-Seq to characterize hippocampal tissue in F0s (n=24, n=6 per phenotype /sex) and F2s (n=250, n=125 per sex) to identify differentially expressed genes related to bHR/bLR lineage and phenotypical behaviors: locomotor response to novelty, anxiety, and Pavlovian Conditioned Approach (PavCA).We found that bHR/bLR phenotypical behaviors remained correlated in the F2s, implying a shared genetic basis. We also found robust differences in hippocampal transcriptional profiles associated with bHR/bLR lineage in the F0s which surpassed the differences associated with sex. These distinct expression profiles were predictive of gene expression patterns associated with F2 bHR/bLR behavior. We then prioritized bHR/bLR differentially expressed genes identified in our current and previous studies as candidates for mediating bHR/bLR phenotypical behaviors in F2s. Seventeen genes were differentially expressed in association with locomotor response to novelty, many of which also had nominal relationships with PavCA behavior. Seven of these genes were located near (+/−1MB) quantitative trait loci for bHR/bLR phenotypical behavior identified in our previous exome sequencing or genome wide association studies: AABR07071904, Ucp2, Ttc30a1, Fzd6, Spg7, Vps9d1, and Afg3l1. We also identified convergence between our model and other genetic rat models targeting internalizing behaviors, with 26 hippocampal genes showing shared patterns of differential expression, including Tmem144 and Mfge8. Our findings provide strong candidates for elucidating genetic and neurobiological factors that may shape differences in temperament and modulate vulnerability to psychiatric and addictive disorders.

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MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGβ5/PI3K/CXCL12 signaling

Cited by 15 publications

References 52 publications

Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats

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MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGβ5/PI3K/CXCL12 signaling

Cited by 15 publications

References 52 publications

Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Extracellular Vesicles from Human Teeth Stem Cells Trigger ATP Release and Promote Migration of Human Microglia through P2X4 Receptor/MFG-E8-Dependent Mechanisms

Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin αVβ5/AMPK signaling pathway after intracerebral hemorrhage in mice

Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F2Cross of Selectively-Bred Rats

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Bioenergetic-Related Gene Expression in the Hippocampus Predicts Internalizing vs. Externalizing Behavior in a F₂Cross of Selectively-Bred Rats