IVIG activates FcγRIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice

Gokce Yilmaz Akyol, Anatol Manaenko, Onat Akyol, Ihsan Solaroglu, Wing Mann Ho, Yan Ding, Jerry Flores, John H. Zhang, Jiping Tang

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Article number15583
Pages (from-to)15583
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - 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

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