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

• DOI: 10.1186/s12974-018-1147-z
• Publication Date: 2018-04-19T15:09:48Z
• Authors: Mingli Liu; Wesley Solomon; Juan Carlos Cespedes; Nana O. Wilson; Byron Ford; Jonathan K. Stiles
• Keywords: ERBB4; Pathogenesis; neuregulin 1; Cerebral Malaria

Human cerebral malaria (HCM) is a severe form of characterized by sequestration infected erythrocytes (IRBCs) in brain microvessels, increased levels circulating free heme and pro-inflammatory cytokines chemokines, swelling, vascular dysfunction, coma, mortality. Neuregulin-1β (NRG-1) encoded the gene NRG1, member family polypeptide growth factors required for normal development nervous system heart. Utilizing an experimental (ECM) model (Plasmodium berghei ANKA C57BL/6), we reported that NRG-1 played cytoprotective role ECM were inversely correlated with severity. Intravenous infusion reduced mortality mice promoting robust anti-inflammatory response coupled reduction accumulation IRBCs microvessels tissue damage.In current study, examined how treatment attenuates pathogenesis associated ECM. We whether protects against CXCL10- heme-induced apoptosis using human microvascular endothelial (hCMEC/D3) cells M059K neuroglial cells. hCMEC/D3 grown monolayer co-culture 30 μM (100 ng/ml) used to examine on blood barrier (BBB) integrity. Using vivo model, was activation ErbB4 AKT inactivation STAT3 signaling pathways. For data analysis, unpaired t test or one-way ANOVA Dunnett's Bonferroni's post applied.We determined cell death/apoptosis neroglial cells, two major components BBB. improved disruption vitro BBB consisting In murine stimulated phosphorylation (pErbB4) followed STAT3, which attenuated mortality.Our results indicate potential pathway maintains integrity vitro, ECM-induced injury, reduces Furthermore, postulate augmenting during therapy may be effective adjunctive reduce CNS injury potentially increase effectiveness anti-malaria (HCM).