TLR3 signaling is either protective or pathogenic for the development of Theiler's virus-induced demyelinating disease depending on the time of viral infection

Background: We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler\u27s murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. Methods: SJL/J and B6; 129S-Tlr3(tm1Flv)/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler\u27s murine encephalomyelitis virus (2 x 10(5) PFU) with or without treatment with 50 mu g of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed. Results: We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4(+) and CD8(+) T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-gamma-producing CD4(+) and CD8(+) T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-gamma-producing CD4(+) and CD8(+) T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3(+) CD4+ T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3(+) CD4(+) T cells. Conclusions: These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction prior to viral infection leads to pathogenesis via over-activation of the pathogenic immune response

Effect of grain boundaries on ion migration in stabilized δ-Bi2O3 thin- film electrolyte

Solid electrolytes with high oxygen-ion conductivity are of significant interest for many applications. Over the past several decades, numerous studies have been conducted on the effect of grain boundaries on the process of increasing the ionic conductivity of solid electrolytes. Given that nanocrystalline thin- or thick-films have been investigated in relation to lowering the operating temperature of solid electrolytes to less than 650 °C, more rigorous and quantitative assessments are necessary to determine how the ion transport characteristics are affected by the numerous interfaces formed in nano-grains devices. Please click Additional Files below to see the full abstract

The Protein Kinase C Inhibitor Aeb071 (Sotrastaurin) Modulates Migration and Superoxide Anion Production by Human Neutrophils In Vitro

We examined the effect of the protein kinase C-selective inhibitor AEB071 (sotrastaurin) on neutrophil functions in vitro. Pre-incubation with AEB071 at concentrations similar to those reached during in vivo therapy significantly reduced cell capacity to migrate toward three different chemo-attractants and to produce superoxide anions (O2) in response to phorbol myristate acetate (PMA) or to iV-formyl-methionyl-leucyl-phenylalanine (fMLP). AEB071 also significantly inhibited the O−2 "overproduction induced by fMLP in neutrophils primed with tumor necrosis factor alpha (TNF-α) or granulocyte/macrophage-colony stimulating factor (GM-CSF). This inhibition was not linked to fMLP-receptor down-regulation since the drug had no effect on either fMLP-receptors or fMLP-induced CD11b membrane expression. When the activity of AEB071 was compared to that of the conventional protein kinase C (PKC) inhibitor Gö6850 (which, like sotrastaurin, inhibits classical and novel PKC isoforms), Gö6976 (an inhibitor of α and β PKC isoforms) and rottlerin (a prevailing δ PKC isoform inhibitor), AEB071 at an equimolar concentration of 3 μM (close to the maximum drug concentration reached in patients treated with AEB071) caused significantly more inhibition on both chemotactic response and superoxide production. These in vitro findings suggest that neutrophils may offer a cellular target for AEB071 activity in vivo