Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior

Guha, Suman K.; Tillu, Rucha; Sood, Ankit; Patgaonkar, Mandar; Nanavaty, I. N.; Sengupta, Arjun; Sharma, Shobhona; Vaidya, Vidita A.; Pathak, Sulabha

doi:10.1016/j.bbi.2014.06.009

Cited by 35 publications

(35 citation statements)

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“…Moreover, in the absence of BBB rupture, an increased production of inflammatory cytokines in CNS, reported after P . chabaudi adami infection, was associated with inhibition of hippocampal neurogenesis, leading to cognitive defects [37]. Here, our results indicate for the first time an early, crucial role of IL-33/ST2 pathway in the development of neuroinflammation affecting neurogenesis during ECM development.…”

Section: Discussionsupporting

confidence: 51%

“…Given that neurogenesis can be influenced by microglia [37], we next explored the status of microglia activation in the absence of ST2 in Pb A-infected mice. Further, changes in microglia architecture may be associated with neuronal deficits [38].…”

Section: Resultsmentioning

confidence: 99%

“…A recent study confirmed that neurogenesis could be affected by activated microglia [37], which in turn might impact the cognitive processes. Here, the significant reduction of neuroblast proliferation in Pb A-infected WT mice was prevented in the absence of IL-33/ST2 pathway, which, in line with the absence of cognitive defect in these mice, confirms a causality link between neurogenesis and cognitive defects.…”

Section: Discussionmentioning

confidence: 96%

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IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria

et al. 2017

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Cerebral malaria (CM) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA)-infection reproduces several of these features. We reported recently increased levels of IL-33 protein in brain undergoing ECM and the involvement of IL-33/ST2 pathway in ECM development. Here we show that PbA-infection induced early short term and spatial memory defects, prior to blood brain barrier (BBB) disruption, in wild-type mice, while ST2-deficient mice did not develop cognitive defects. PbA-induced neuroinflammation was reduced in ST2-deficient mice with low Ifng, Tnfa, Il1b, Il6, CXCL9, CXCL10 and Cd8a expression, associated with an absence of neurogenesis defects in hippocampus. PbA-infection triggered a dramatic increase of IL-33 expression by oligodendrocytes, through ST2 pathway. In vitro, IL-33/ST2 pathway induced microglia expression of IL-1β which in turn stimulated IL-33 expression by oligodendrocytes. These results highlight the IL-33/ST2 pathway ability to orchestrate microglia and oligodendrocytes responses at an early stage of PbA-infection, with an amplification loop between IL-1β and IL-33, responsible for an exacerbated neuroinflammation context and associated neurological and cognitive defects.

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Section: Discussionsupporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria

et al. 2017

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“…Further supporting this interpretation, mice infected with the mild parasite Plasmodium chabaudi adami also transiently demonstrated behavioural defects, generalized microglial activation, and decreased neurogenesis despite the absence of gross cerebral vascular leakage [48]. Additionally, P. chabaudi adami -infected animals displayed elevated levels of pro-inflammatory cytokines in brain tissue during the peak of infection (day 9 post-infection), which resolved during the recovery phase (day 15 post-infection) [48]. These data, together with the present study, suggest that while relatively mild levels of inflammation may result in transiently altered behaviour, a certain threshold is required to enact irreparable damage and eventual death.…”

Section: Discussionmentioning

confidence: 95%

“…Furthermore, this suggests that infiltration of pathological immune cells may not be necessary to affect neurological function. Further supporting this interpretation, mice infected with the mild parasite Plasmodium chabaudi adami also transiently demonstrated behavioural defects, generalized microglial activation, and decreased neurogenesis despite the absence of gross cerebral vascular leakage [48]. Additionally, P. chabaudi adami -infected animals displayed elevated levels of pro-inflammatory cytokines in brain tissue during the peak of infection (day 9 post-infection), which resolved during the recovery phase (day 15 post-infection) [48].…”

Section: Discussionmentioning

confidence: 95%

Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi

Wilson

Stutz

Ochoa

et al. 2016

Malar J

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BackgroundCerebral malaria is one of the most severe complications of Plasmodium falciparum infection and occurs mostly in young African children. This syndrome results from a combination of high levels of parasitaemia and inflammation. Although parasite sequestration in the brain is a feature of the human syndrome, sequestering strains do not uniformly cause severe malaria, suggesting interplay with other factors. Host genetic factors such as mutations in the promoters of the cytokines IL-10 and TNF are also clearly linked to severe disease. Plasmodium chabaudi, a rodent malaria parasite, leads to mild illness in wildtype animals. However, IL-10−/− mice respond to parasite with increased levels of pro-inflammatory cytokines IFN-γ and TNF, leading to lethal disease in the absence of sequestration in the brain. These mice also exhibit cerebral symptoms including gross cerebral oedema and haemorrhage, allowing study of these critical features of disease without the influence of sequestration.MethodsThe neurological consequences of P. chabaudi infection were investigated by performing a general behavioural screen (SHIRPA). The immune cell populations found in the brain during infection were also analysed using flow cytometry and confocal microscopy.ResultsIL-10−/− mice suffer significant declines in behavioural and physical capacities during infection compared to wildtype. In addition, grip strength and pain sensitivity were affected, suggestive of neurological involvement. Several immune cell populations were identified in the perfused brain on day 7 post-infection, suggesting that they are tightly adherent to the vascular endothelium, or potentially located within the brain parenchyma. There was an increase in both inflammatory monocyte and resident macrophage (CD11bhi, CD45+, MHCII+, Ly6C+/−) numbers in IL-10−/− compared to wildtype animals. In addition, the activation state of all monocytes and microglia (CD11bint, CD45−, MHC-II+) were increased. T cells making IFN-γ were also identified in the brain, but were localized within the vasculature, and not the parenchyma.ConclusionsThese studies demonstrate exacerbated neuroinflammation concurrent with development of behavioural symptoms in P. chabaudi infection of IL-10−/− animals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1477-1) contains supplementary material, which is available to authorized users.

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Induction of Neuroinflammation and Neurotoxicity by Synthetic Hemozoin

2019

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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.Electronic supplementary materialThe online version of this article (10.1007/s10571-019-00713-4) contains supplementary material, which is available to authorized users.

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Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior

Cited by 35 publications

References 123 publications

IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria

IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria

Behavioural and neurological symptoms accompanied by cellular neuroinflammation in IL-10-deficient mice infected with Plasmodium chabaudi

Induction of Neuroinflammation and Neurotoxicity by Synthetic Hemozoin

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