Abstract
Following intracerebral hemorrhage (ICH), the activation of mast cell contributes to brain inflammation and brain injury. The mast cell activation is negatively regulated by an inhibitory IgG-receptor. It's signals are mediated by SHIP (Src homology 2-containing inositol 5′ phosphatase), in particular SHIP1, which activation leads to hydrolyzation of PIP3 (Phosphatidylinositol (3,4,5)-Trisphosphate (PtdIns(3,4,5)P3, leading to the inhibition of calcium mobilization and to the attenuation of mast cell activation. Intravenous immunoglobulin (IVIG) is a FDA-Approved drug containing IgG. We hypothesized that IVIG will attenuate the ICH-induced mast cell activation via FcγRIIB/SHIP1 pathway, resulting in a decrease of brain inflammation, protection of the blood-brain-barrier, and improvement of neurological functions after ICH. To prove this hypothesis we employed the ICH collagenase mouse model. We demonstrated that while ICH induced mast cell activation/degranulation, IVIG attenuated post-ICH mast cell activation. Mast cell deactivation resulted in reduced inflammation, consequently attenuating brain edema and improving of neurological functions after ICH. Furthermore using siRNA-induced in vivo knockdown approach we demonstrated that beneficial effects of IVIG were mediated, at least partly, via SHIP1/PIP3 pathway. We conclude that IVIG treatment represents a promising therapeutic approach potentially able to decrease mortality and morbidity after ICH in experimental models.
Original language | English |
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Article number | 15583 |
Pages (from-to) | 15583 |
Journal | Scientific Reports |
Volume | 7 |
Issue number | 1 |
DOIs | |
State | Published - Nov 14 2017 |
ASJC Scopus Subject Areas
- General
Keywords
- Phosphatidylinositol Phosphates/metabolism
- Humans
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/genetics
- RNA, Small Interfering/genetics
- Signal Transduction/drug effects
- Brain/drug effects
- Calcium/metabolism
- Immunoglobulin G/administration & dosage
- Receptors, IgG/genetics
- Administration, Intravenous
- Animals
- Blood-Brain Barrier/drug effects
- Cerebral Hemorrhage/drug therapy
- Inflammation/drug therapy
- Mice
- Mast Cells/drug effects
- Collagenases/genetics
- Disease Models, Animal