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Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy.

ABSTRACT: Blood-brain barrier (BBB) disruption is associated with hypoxia-ischemia (HI) induced brain injury and life-long neurological pathologies. Treatment options are limited. Recently, we found that mesenchymal stem/stromal cell derived extracellular vesicles (MSC-EVs) protected the brain in ovine fetuses exposed to HI. We hypothesized that Annexin A1 (ANXA1), present in MSC-EVs, contributed to their therapeutic potential by targeting the ANXA1/Formyl peptide receptor (FPR), thereby preventing loss of the BBB integrity. Cerebral ANXA1 expression and leakage of albumin into the fetal ovine brain parenchyma after HI were analyzed by immunohistochemistry. For mechanistic insights, barrier integrity of primary fetal endothelial cells was assessed after oxygen-glucose deprivation (OGD) followed by treatment with MSC-EVs or human recombinant ANXA1 in the presence or absence of FPR inhibitors. Our study revealed that BBB integrity was compromised after HI which was improved by MSC-EVs containing ANXA1. Treatment with these MSC-EVs or ANXA1 improved BBB integrity after OGD, an effect abolished by FPR inhibitors. Furthermore, endogenous ANXA1 was depleted within 24 h after induction of HI in cerebovasculature and ependyma and upregulated 72 h after HI in microglia. Targeting ANXA1/FPR with ANXA1 in the immature brain has great potential in preventing BBB loss and concomitant brain injury following HI.

SUBMITTER: Gussenhoven R

PROVIDER: S-EPMC6406389 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy.

Gussenhoven Ruth R Klein Luise L Ophelders Daan R M G DRMG Habets Denise H J DHJ Giebel Bernd B Kramer Boris W BW Schurgers Leon J LJ Reutelingsperger Chris P M CPM Wolfs Tim G A M TGAM

Journal of clinical medicine 20190124 2

Blood-brain barrier (BBB) disruption is associated with hypoxia-ischemia (HI) induced brain injury and life-long neurological pathologies. Treatment options are limited. Recently, we found that mesenchymal stem/stromal cell derived extracellular vesicles (MSC-EVs) protected the brain in ovine fetuses exposed to HI. We hypothesized that Annexin A1 (ANXA1), present in MSC-EVs, contributed to their therapeutic potential by targeting the ANXA1/Formyl peptide receptor (FPR), thereby preventing loss o ...[more]

PMID: 30682787

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Project description:Interferon regulatory factor 4 (IRF4), a transcription factor recognized as a key regulator of lymphoid and myeloid cell differentiation, has recently been recognized as a critical mediator of macrophage activation. Previously we have reported that IRF4 signaling is closely correlated with anti-inflammatory polarization of microglia in adult mice after stroke. However, IRF4's role in the inflammatory response in the immature brain is unknown. Using a model of neonatal hypoxic ischemic encephalopathy (HIE) we investigated the regulatory action of IRF4 signaling in the activation of microglia and monocytes after HIE. IRF4 myeloid cell conditional knockout (CKO) postnatal day 10 (P10) male pups were subjected to a 60-min hypoxic-ischemic insult by the Rice-Vanucci model (RVM). IRF4 gene floxed mice (IRF4fl/fl) were used as controls. Brain atrophy and behavioral deficits were measured 7 days after HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune cell responses by both cell membrane and intracellular marker staining. Serum levels of cytokines were determined by ELISA. The results showed that IRF4 CKO pups had increased tissue loss and worse behavioral deficits than IRF4fl/fl mice seven days after HIE. FC demonstrated significantly more infiltration of monocytes and neutrophils in the ischemic brains of IRF4 CKO vs IRF4fl/fl pups. IRF4 CKO ischemic microglia were more pro-inflammatory as evidenced by higher expression of the pro-inflammatory marker CD68, and increased intracellular TNF? and IL-1? levels compared to controls. In addition, IRF4 deletion from myeloid cells resulted in increased levels of circulating pro-inflammatory cytokines and higher endothelial MMP9 expression after HIE. These data indicate that IRF4 signaling in myeloid cells plays a regulatory role in neuroinflammation and that deletion of myeloid IRF4 is detrimental to HIE injury, suggesting that IRF4 could serve as a potential therapeutic target for neonatal ischemic brain injury.

Dataset Information

Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy.

Publications

Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy.

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