CD47 blocking antibody accelerates hematoma clearance and alleviates hydrocephalus after experimental intraventricular hemorrhage

https://doi.org/10.1016/j.nbd.2021.105384Get rights and content
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Highlights

  • CD47 blocking antibody accelerated hematoma clearance following IVH.

  • CD47 blocking antibody alleviated IVH-induced hydrocephalus.

  • CD47 blocking antibody reduced hemolysis in the clot after IVH.

Abstract

Background

CD47, a glycoprotein on red blood cell membranes, inhibits phagocytosis via interaction with signal regulatory protein α on phagocytes. Our previous research has demonstrated that blocking CD47 accelerates hematoma clearance and reduces brain injury after intracerebral hemorrhage. The current study investigated whether phagocytosis or erythrocyte CD47 impacts hematoma resolution and hydrocephalus development after intraventricular hemorrhage (IVH).

Methods

Adult (3-month-old) male Fischer 344 rats were intraventricularly injected with 200 μl autologous blood, mixed with either CD47 blocking antibody or isotype IgG, or 200 μl saline as control. In subgroups of CD47 blocking antibody treated rats, clodronate liposomes (to deplete microglia/monocyte-derived macrophages) or control liposomes were co-injected. Magnetic resonance imaging (MRI) was used to evaluate ventricular volume and intraventricular T2* lesion volume (estimating hematoma volume). The brains were harvested after 4 or 72 h for histology to evaluate phagocytosis.

Results

In adult male rats, CD47 blocking antibody alleviated hydrocephalus development by day 3. In addition, the CD47 blocking antibody reduced intraventricular T2* lesion and T2* non-hypointense lesion size after IVH through day 1 to day 3. Erythrophagocytosis was observed as soon as 4 h after IVH and was enhanced on day 3. Furthermore, intra-hematoma infiltration of CD68, heme oxygenase-1 and ferritin positive phagocytes were upregulated by CD47 blockade by day 3. Clodronate liposomes co-injection caused more severe hydrocephalus and weight loss.

Conclusion

Blocking CD47 in the hematoma accelerated hematoma clearance and alleviated hemolysis and hydrocephalus development after IVH, suggesting CD47 might be valuable in the future treatment for IVH.

Keywords

CD47 blocking antibody
Hydrocephalus
Intraventricular hemorrhage
Macrophage

Abbreviations

IVH
Intraventricular hemorrhage
MRI
Magnetic resonance imaging
ICH
Intracerebral hemorrhage
SAH
Subarachnoid hemorrhage
CSF
Cerebrospinal fluid
PHH
Post-hemorrhagic hydrocephalus
rt-PA
Recombinant tissue plasminogen activator
M/Mo-MΦ
Microglia/Monocyte-derived macrophages
RBC
Red blood cell
SIRP α
Signal regulatory protein α
H&E
Hematoxylin and eosin
HO-1
Heme oxygenase-1
DAPI
4′, 6-diamidino-2-phenylindole
SD
Standard deviation

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