Abstract
Hemozoin produced by Plasmodium falciparum during malaria infection has been linked to the neurological dysfunction in cerebral malaria. In this study, we determined whether a synthetic form of hemozoin (sHZ) produces neuroinflammation and neurotoxicity in cellular models. Incubation of BV-2 microglia with sHZ (200 and 400 µg/ml) induced significant elevation in the levels of TNFα, IL-6, IL-1β, NO/iNOS, phospho-p65, accompanied by an increase in DNA binding of NF-κB. Treatment of BV-2 microglia with sHZ increased protein levels of NLRP3 with accompanying increase in caspase-1 activity. In the presence of NF-κB inhibitor BAY11-7082 (10 µM), there was attenuation of sHZ-induced release of pro-inflammatory cytokines, NO/iNOS. In addition, increase in caspase-1/NLRP3 inflammasome activation was blocked by BAY11-7082. Pre-treatment with BAY11-7082 also reduced both phosphorylation and DNA binding of the p65 sub-unit. The NLRP3 inhibitor CRID3 (100 µM) did not prevent sHZ-induced release of TNFα and IL-6. However, production of IL-1β, NO/iNOS as well as caspase-1/NLRP3 activity was significantly reduced in the presence of CRID3. Incubation of differentiated neural progenitor (ReNcell VM) cells with sHZ resulted in a reduction in cell viability, accompanied by significant generation of cellular ROS and increased activity of caspase-6, while sHZ-induced neurotoxicity was prevented by N-acetylcysteine and Z-VEID-FMK. Taken together, this study shows that the synthetic form of hemozoin induces neuroinflammation through the activation of NF-κB and NLRP3 inflammasome. It is also proposed that sHZ induces ROS- and caspase-6-mediated neurotoxicity. These results have thrown more light on the actions of malarial hemozoin in the neurobiology of cerebral malaria.
Highlights
Microglia-mediated neuroinflammation is associated with the pathogenesis of a wide range of brain disorders resulting in the release of neurotoxic chemicals which produce adverse effects on adjacent neurons
Results showing that synthetic form of hemozoin (sHZ) could induce the release of proIL-1β/IL-1β in BV-2 microglia led us to investigate any role played by the activation of NLRP3 inflammasome
Using the inflammasome Glo assay which measures the activity of caspase-1, we show in Fig. 4a that exposure of BV-2 microglia to sHZ (200 and 400 μg/ml) resulted in significant increases in caspase-1 activity
Summary
Microglia-mediated neuroinflammation is associated with the pathogenesis of a wide range of brain disorders resulting in the release of neurotoxic chemicals which produce adverse effects on adjacent neurons. A high incidence of neurocognitive impairment was reported in cerebral malaria (Idro et al 2005; Murray et al 2012) This cognitive deficit has been linked to parasite sequestration in the CNS and activation of inflammatory responses mediated by neurotoxic factors such as nitric oxide (NO), tumor necrosis factor alpha (TNFα), gamma interferon (IFNγ), interleukin-6 (IL-6) and interleukin-1β (IL-1β) which damage adjacent neurons (Brown et al 1999; McCall and Sauerwein 2010; Sahu et al 2013). There have been reports showing that autopsy materials of patients who died of cerebral malaria, as well as brain of mice with cerebral malaria contain activated microglia (Medana et al 2002; Wiese et al 2006)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
