Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling

Autor: Byron D. Ford, Juan Carlos Cespedes, Nana O. Wilson, Mingli Liu, Wesley Solomon, Jonathan K. Stiles
Rok vydání: 2017
Předmět:
0301 basic medicine
Chemokine
Receptor
ErbB-4
Apoptosis
Inbred C57BL
Cardiovascular
lcsh:RC346-429
STAT3
Mice
ErbB4
0302 clinical medicine
ErbB-4
Claudin-5
Cerebral malaria
Cells
Cultured
Cultured
biology
General Neuroscience
3. Good health
medicine.anatomical_structure
Infectious Diseases
Neurology
Cerebral Malaria
Drug
Receptor
Signal Transduction
STAT3 Transcription Factor
Programmed cell death
Cerebral
Cells
Neuregulin-1
Clinical Sciences
Immunology
P. berghei ANKA (PbA)
Malaria
Cerebral
Neuregulin-1 (NRG-1)
Blood–brain barrier
Dose-Response Relationship
03 medical and health sciences
Cellular and Molecular Neuroscience
Rare Diseases
medicine
CXCL10
Animals
Humans
Plasmodium berghei
Neuregulin 1
Protein kinase B
lcsh:Neurology. Diseases of the nervous system
Neurology & Neurosurgery
Dose-Response Relationship
Drug
business.industry
Animal
Research
AKT
Neurosciences
Epithelial Cells
biology.organism_classification
Coculture Techniques
Malaria
Brain Disorders
Vector-Borne Diseases
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Good Health and Well Being
Disease Models
Hemangioendothelioma
Cerebral malaria (CM)
biology.protein
Cancer research
P. berghei ANKA
business
Proto-Oncogene Proteins c-akt
030217 neurology & neurosurgery
Zdroj: Journal of Neuroinflammation
Journal of neuroinflammation, vol 15, iss 1
Journal of Neuroinflammation, Vol 15, Iss 1, Pp 1-15 (2018)
ISSN: 1742-2094
Popis: Background Human cerebral malaria (HCM) is a severe form of malaria characterized by sequestration of infected erythrocytes (IRBCs) in brain microvessels, increased levels of circulating free heme and pro-inflammatory cytokines and chemokines, brain swelling, vascular dysfunction, coma, and increased mortality. Neuregulin-1β (NRG-1) encoded by the gene NRG1, is a member of a family of polypeptide growth factors required for normal development of the nervous system and the heart. Utilizing an experimental cerebral malaria (ECM) model (Plasmodium berghei ANKA in C57BL/6), we reported that NRG-1 played a cytoprotective role in ECM and that circulating levels were inversely correlated with ECM severity. Intravenous infusion of NRG-1 reduced ECM mortality in mice by promoting a robust anti-inflammatory response coupled with reduction in accumulation of IRBCs in microvessels and reduced tissue damage. Methods In the current study, we examined how NRG-1 treatment attenuates pathogenesis and mortality associated with ECM. We examined whether NRG-1 protects against CXCL10- and heme-induced apoptosis using human brain microvascular endothelial (hCMEC/D3) cells and M059K neuroglial cells. hCMEC/D3 cells grown in a monolayer and a co-culture system with 30 μM heme and NRG-1 (100 ng/ml) were used to examine the role of NRG-1 on blood brain barrier (BBB) integrity. Using the in vivo ECM model, we examined whether the reduction of mortality was associated with the activation of ErbB4 and AKT and inactivation of STAT3 signaling pathways. For data analysis, unpaired t test or one-way ANOVA with Dunnett’s or Bonferroni’s post test was applied. Results We determined that NRG-1 protects against cell death/apoptosis of human brain microvascular endothelial cells and neroglial cells, the two major components of BBB. NRG-1 treatment improved heme-induced disruption of the in vitro BBB model consisting of hCMEC/D3 and human M059K cells. In the ECM murine model, NRG-1 treatment stimulated ErbB4 phosphorylation (pErbB4) followed by activation of AKT and inactivation of STAT3, which attenuated ECM mortality. Conclusions Our results indicate a potential pathway by which NRG-1 treatment maintains BBB integrity in vitro, attenuates ECM-induced tissue injury, and reduces mortality. Furthermore, we postulate that augmenting NRG-1 during ECM therapy may be an effective adjunctive therapy to reduce CNS tissue injury and potentially increase the effectiveness of current anti-malaria therapy against human cerebral malaria (HCM).
Databáze: OpenAIRE
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