Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling
Abstract 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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-04-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1147-z |
| _version_ | 1818982930317312000 |
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| author | Mingli Liu Wesley Solomon Juan Carlos Cespedes Nana O. Wilson Byron Ford Jonathan K. Stiles |
| author_facet | Mingli Liu Wesley Solomon Juan Carlos Cespedes Nana O. Wilson Byron Ford Jonathan K. Stiles |
| author_sort | Mingli Liu |
| collection | DOAJ |
| description | Abstract 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). |
| first_indexed | 2024-12-20T17:55:02Z |
| format | Article |
| id | doaj.art-53453936245d4108a72748a19512b396 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T17:55:02Z |
| publishDate | 2018-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-53453936245d4108a72748a19512b3962022-12-21T19:30:47ZengBMCJournal of Neuroinflammation1742-20942018-04-0115111510.1186/s12974-018-1147-zNeuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signalingMingli Liu0Wesley Solomon1Juan Carlos Cespedes2Nana O. Wilson3Byron Ford4Jonathan K. Stiles5Department of Microbiology, Biochemistry and Immunology, Morehouse School of MedicineDepartment of Microbiology, Biochemistry and Immunology, Morehouse School of MedicineDepartment of Microbiology, Biochemistry and Immunology, Morehouse School of MedicineFogarty Global Health Fellow (UJMT), Morehouse School of MedicineDivision of Biomedical Sciences, University of California-Riverside School of MedicineDepartment of Microbiology, Biochemistry and Immunology, Morehouse School of MedicineAbstract 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).http://link.springer.com/article/10.1186/s12974-018-1147-zCerebral malaria (CM)Neuregulin-1 (NRG-1)ErbB4STAT3AKTP. berghei ANKA (PbA) |
| spellingShingle | Mingli Liu Wesley Solomon Juan Carlos Cespedes Nana O. Wilson Byron Ford Jonathan K. Stiles Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling Journal of Neuroinflammation Cerebral malaria (CM) Neuregulin-1 (NRG-1) ErbB4 STAT3 AKT P. berghei ANKA (PbA) |
| title | Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling |
| title_full | Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling |
| title_fullStr | Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling |
| title_full_unstemmed | Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling |
| title_short | Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling |
| title_sort | neuregulin 1 attenuates experimental cerebral malaria ecm pathogenesis by regulating erbb4 akt stat3 signaling |
| topic | Cerebral malaria (CM) Neuregulin-1 (NRG-1) ErbB4 STAT3 AKT P. berghei ANKA (PbA) |
| url | http://link.springer.com/article/10.1186/s12974-018-1147-z |
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