MHCI binding to PirB facilitates tyrosine phosphorylation of PirB

MHCI binding to PirB facilitates tyrosine phosphorylation of PirB on cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, which in turn recruits SHP-1 and SHP-2 phosphatases to PirB and modulates

downstream signal transduction pathways (Nakamura et al., 2004 and Takai, 2005). Therefore, we examined whether upregulation of Kb, Db, β2m, and PirB after MCAO is associated with known PirB signaling components in the brain (Syken et al., 2006). Both PirB phosphorylation and SHP-2 recruitment to PirB increase significantly after MCAO (Figures 3I and 3J). Thus, a notable consequence of MCAO is to engage the Selleckchem Carfilzomib first key steps in PirB downstream signal transduction. PirB and KbDb KO mice have smaller infarcts and better motor recovery, suggesting that these molecules exert their deleterious effects in WT both by causing more cell death within the infarct and by limiting compensation via synaptic plasticity in surviving circuits. Because Kb, Db, and PirB also

function in the immune system, the smaller infarcts seen in KO mice might arise from a dysregulated immune response (Maenaka and Jones, 1999 and Takai, 2005), rather than from absence of expression in the CNS. To examine this possibility, we employed an in vitro model of ischemia: 15 min of oxygen glucose deprivation (OGD) of hippocampal organotypic slice cultures. The slices contain resident astrocytes and microglia but few if any peripheral immune cells. Circulating neutrophils, which might be present initially within these slices, have life spans of only 8–20 hr, and so are gone prior to experiments, which start after 2 weeks mafosfamide in vitro; Selleck Epacadostat no new peripheral immune cells can infiltrate in response to injury. The extent of neuronal cell death was assessed directly in CA1 by using propidium iodide (PI) immunofluorescence 24 hr after OGD insult (Ouyang et al., 2007; Figure 4A). Despite the absence of peripheral immune system infiltration, cultures from KbDb WT mice sustained significant damage, whereas cell death was significantly reduced

in cultures from KbDb KO mice, as indicated by a 55% decrease in average PI fluorescence intensity (KbDb KO: 38 ± 1.9 median pixel intensity versus WT: 89 ± 3.4; p < 0.0001; Figure 4A). Cultures from PirB KO mice also had less cell death than WT, visualized as a 54% decrease in average PI fluorescence intensity compared to WT (PirB KO: 64 ± 3.7 median pixel intensity versus WT: 141 ± 7.3; p < 0.0001; Figure 4B). These observations demonstrate that in vitro as well as in vivo, PirB, Kb, and Db contribute to damage after ischemia. In addition, results suggest that, in vivo, the absence of these molecules in brain cells (neurons and/or resident glia), rather than just in the peripheral immune system, is neuroprotective. Functional recovery after stroke is associated with axonal plasticity as well as with altered gene expression profiles (Lee et al., 2004, Li et al., 2010, Netz et al., 1997 and Stinear et al.

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