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CD36 participates in PrP(106-126)-induced activation of microglia.

ABSTRACT: Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106-126 (PrP(106-126)). We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126) in BV2 microglia. We then analyzed different parameters of microglial activation in PrP(106-126)-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP(106-126). The results showed that PrP(106-126) treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1?, IL-6 and TNF-?), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-?B and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP(106-126)-stimulated NF-?B activation and TNF-? protein release, abrogated the PrP(106-126)-induced iNOS stimulation, downregulated IL-1? and IL-6 expression at both mRNA and protein levels as well as TNF-? mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP(106-126)-treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP(106-126). Together, these results suggest that CD36 is involved in PrP(106-126)-induced microglial activation and that the participation of CD36 in the interaction between PrP(106-126) and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling.

SUBMITTER: Kouadir M

PROVIDER: S-EPMC3266924 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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CD36 participates in PrP(106-126)-induced activation of microglia.

Kouadir Mohammed M Yang Lifeng L Tan Rongrong R Shi Fushan F Lu Yun Y Zhang Siming S Yin Xiaomin X Zhou Xiangmei X Zhao Deming D

PloS one 20120126 1

Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106-126 (PrP(106-126)). We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126) in BV2 microglia. We then analyz ...[more]

PMID: 22292032

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Project description:Prion-related encephalopathies are characterized by the intracerebral accumulation of an abnormal isoform of the cellular prion protein (PrPC) named scrapie prion protein (PrPSc). The pathological forms of this protein and its cellular precursor are not only expressed in the brain but also, at lower concentrations, in peripheral tissues. We recently showed that a synthetic peptide corresponding to residues 106-126 [PrP-(106-126)] of the human PrP is toxic to neurons and trophic to astrocytes in vitro. Our experiments were aimed at verifying whether PrP-(106-126) and other peptides corresponding to fragments of the amyloid protein purified from brains of patients with Gerstmann-Sträussler-Scheinker disease-namely PrP-(89-106), PrP-(106-114), PrP-(127-147)-were capable of stimulating circulating leucocytes. Native PrP expression in human lymphocytes, monocytes and neutrophils was first confirmed using PCR amplification of total RNA, after reverse transcription, and immunoblot analysis of cell extracts with anti-PrP antibodies. PrP-(106-126), but not the other peptides, increased membrane microviscosity, intracellular Ca2+ concentration and cell migration in circulating leucocytes, and O2-. production in monocytes and neutrophils. Membrane microviscosity was determined by the fluorescence polarization technique, using diphenylhexatriene as a probe, 300 s after the addition of PrP-(106-126) to the cell suspension in the concentration range 5-50 microM. The increase in intracellular Ca2+ elicited by PrP-(106-126) was dose-dependent in the range 5-500 microM. PrP-(106-126) stimulated O2-. production in monocytes and neutrophils in a dose- (10-300 microM) and time-(5-30 min) dependent manner in the presence of 10 microM dihydrocytochalasin B. Both the increase in Ca2+ concentration and the O2-. production were partially sensitive to pertussis toxin. PrP-(106-126) stimulated leucocyte migration in a dose-dependent (30-300 microM) manner and, at the highest concentration used, this migration was comparable with that elicited by 2.5 nM interleukin 8 or 10 nM fMet-Leu-Phe peptide.

Project description:BackgroundMicroglia and macrophages (MG/M?) have a diverse range of functions depending on unique cytokine stimuli, and contribute to neural cell death, repair, and remodeling during central nervous system diseases. While IL-1 has been shown to exacerbate inflammation, it has also been recognized to enhance neuroregeneration. We determined the activating phenotype of MG/M? and the impact of IL-1 in an in vivo spinal cord injury (SCI) model of IL-1 knock-out (KO) mice. Moreover, we demonstrated the contribution of IL-1 to both the classical and alternative activation of MG in vitro using an adult MG primary culture.MethodsSCI was induced by transection of the spinal cord between the T9 and T10 vertebra in wild-type and IL-1 KO mice. Locomotor activity was monitored and lesion size was determined for 14 days. TNF? and Ym1 levels were monitored to determine the MG/M? activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFN? or IL-4 with and without IL-1?. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1?.ResultsThe locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNF? production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/M? marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/M?. We treated primary MG cultures with IFN? or IL-4 in the presence and absence of IL-1?. Increased nitric oxide and TNF? was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFN? and IL-1?. Expression of the alternative activation markers Ym1 and arginase-1 was increased after exposure to IL-4 and further increased after co-treatment with IL-4 and IL-1?. The phenotype was not observed after exposure of cells to IL-13.ConclusionsWe demonstrate here in in vivo experiments that IL-1 suppressed SCI in a process mediated by the reduction of inflammatory responses. Moreover, we suggest that IL-1 participates in both the classical and alternative activation of MG in in vivo and in vitro systems.

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CD36 participates in PrP(106-126)-induced activation of microglia.

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CD36 participates in PrP(106-126)-induced activation of microglia.

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