IVIG activates FcγRIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice
Open accessAbstract
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)P 3, 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.
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3-alpha-Aminocholestane (3AC) is a selective inhibitor of INPP5D.
“Here, we used 3-alpha-Aminocholestane (3AC), a compound previously reported to be a selective inhibitor of INPP5D39, which has been utilized in several studies to reduce INPP5D activity in vivo in mice and in vitro cell culture39–47.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [44]
The Treatment regimen and interventions section (page not available) identifies 3α-aminocholestane (3AC) as a SHIP1 inhibitor used in mice, and the Discussion describes its use to inhibit SHIP1. The paper does not state that 3AC is selective for INPP5D or report a selectivity comparison, so it supports the inhibitor identification but not the selectivity claim. (LLM, conf=0.86)
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- Authors
- Akyol, G. Y., Manaenko, A., Akyol, O., Solaroglu, I., Ho, W. M., Ding, Y., Flores, J., Zhang, J. H., & Tang, J.
- Affiliations
- Loma Linda University (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Tang, Jiping
- Venue
- Scientific Reports
- Published
- 2017-11-14
- Volume
- 7
- Issue
- 1
- Pages
- 15583-15583
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5686215
- OpenAlex
- W2767545495
- Cited by
- 25
- References
- 63
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 1 · 2018: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (5p01ns082184-05, P01 NS082184-01, NS082184)
- National Institute of Neurological Disorders and Stroke (P01 NS-082184)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- intravenous immunoglobulin, intracerebral hemorrhage, mast cell activation, FcγRIIB, SHIP1, phosphatidylinositol 3,4,5-trisphosphate, neuroinflammation, blood-brain barrier, cerebral edema, neurological function
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Blood-Brain Barrier, Brain, Calcium, Cerebral Hemorrhage, Disease Models, Animal, Humans, Immunoglobulin G, Inflammation, Mast Cells, Signal Transduction, Collagenases, Receptors, IgG, Phosphatidylinositol Phosphates, RNA, Small Interfering, Mice, Administration, Intravenous
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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