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Isolation and Analysis of Brain-sequestered Leukocytes from Plasmodium berghei ANKA-infected Mice
Published on: January 2, 2013
IL-33 receptor ST2 regulates the cognitive impairments associated with experimental cerebral malaria
Flora Reverchon1,2, Stéphane Mortaud1,2, Maëliss Sivoyon1,2
1CNRS, UMR7355, Orleans, France.
Abstract:
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.
Insights
Interleukin-33 (IL-33) signaling drives early cognitive deficits in experimental cerebral malaria (ECM) by promoting neuroinflammation. Blocking this pathway protects against memory impairment and brain inflammation in mice.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Cerebral malaria (CM) causes significant mortality and long-term neurocognitive issues.
- The murine model of experimental cerebral malaria (ECM) mirrors human CM features.
- The IL-33/ST2 pathway is implicated in ECM development.
Purpose of the Study:
- To investigate the role of the IL-33/ST2 pathway in early cognitive deficits during ECM.
- To elucidate the cellular mechanisms underlying IL-33-mediated neuroinflammation in ECM.
Main Methods:
- Utilized Plasmodium berghei ANKA (PbA)-infected wild-type and ST2-deficient mice.
- Assessed cognitive function (short-term and spatial memory) and neuroinflammation markers.
- Examined gene and protein expression in brain tissue, including hippocampus.
- Conducted in vitro experiments with microglia and oligodendrocytes.
Main Results:
- PbA infection caused early memory deficits in wild-type mice, absent in ST2-deficient mice.
- ST2 deficiency reduced neuroinflammation, cytokine expression (IFN-γ, TNF-α, IL-1β, IL-6), and protected hippocampal neurogenesis.
- IL-33 expression increased in oligodendrocytes during ECM, mediated by the ST2 pathway.
- An IL-33/ST2-driven amplification loop involving IL-1β from microglia and IL-33 from oligodendrocytes was identified.
Conclusions:
- The IL-33/ST2 pathway orchestrates early microglial and oligodendrocyte responses in PbA-induced ECM.
- This pathway exacerbates neuroinflammation and contributes to neurological and cognitive deficits.
- Targeting the IL-33/ST2 pathway may offer therapeutic potential for CM-associated cognitive impairment.
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