Abstract
BackgroundHuman 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.MethodsIn 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.ResultsWe 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.ConclusionsOur 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).
Highlights
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
We have reported that elevation of circulating CXCL10 and free heme induce apoptosis of human brain microvascular endothelial cells and astroglia/neuroglia (M059K) [6, 7], indicating the important roles played by circulating CXCL10 and free heme in mediating experimental cerebral malaria (ECM) and HCM pathogenesis, blood brain barrier (BBB) integrity, and mortality [8, 9]
NRG-1 protects against CXCL10- and heme-induced apoptosis in astrocytes and endothelial cells We previously reported that mortality associated with HCM correlates with increased serum CXCL10 levels and that treatment of both endothelial hCMEC/D3 and neuroglial M059K cells with CXCL10 at a physiologically relevant concentration of 0.02 μg/ml in vitro induced apoptosis [6]
Summary
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. The BBB is a highly selective semipermeable membrane barrier consisting of cerebral vascular endothelial cells and astrocytes surrounding them. It separates the circulating blood from the brain and extracellular fluid [3] and protects neural tissues against various unfavorable compositions and toxins in the blood. We have reported that elevation of circulating CXCL10 and free heme induce apoptosis of human brain microvascular endothelial cells (hCMEC/D3) and astroglia/neuroglia (M059K) [6, 7], indicating the important roles played by circulating CXCL10 and free heme in mediating experimental cerebral malaria (ECM) and HCM pathogenesis, BBB integrity, and mortality [8, 9]
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