Abstract
The detailed knowledge about the contribution of immunoproteasome to the neuroinflammation in ischemic stroke is still not available. The immunoreactivity of low molecular mass peptide 2 (LMP2) and low molecular mass peptide 7 (LMP7) was evident in the ipsilateral ischemic cerebral cortex and striatum following transient middle cerebral artery occlusion (MCAO). Both LMP2 and LMP7 increased as early as 4 h after the MCAO, further increased at 24 h, peaked at 72 h and decreased 7 days later. LMP2 and LMP7 were mainly present in astrocytes and microglia/macrophage cells, respectively. LMP2 knockdown by shRNA (short hairpin RNA) markedly reduced the levels of LMP2 and LMP7 protein and caused 75.5 and 78.6% decrease in the caspase-like (C-L) and chymotrypsin-like (CT-L) activities, respectively. Compared with cont-shRNA group (39.7%, infarction volumes/total ipsilateral hemisphere), the infarction volumes were reduced to 22.5% in LMP2-shRNA group. Additionally, LMP2 knockdown significantly reduced activated astrocytes and microglia, the expression nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and caused less accumulation of ischemia-induced protein ubiquitination compared with MG132. These findings demonstrate that inhibition of LMP2 significantly attenuates inflammatory reaction and offers neuroprotection against focal cerebral ischemia in rats, suggesting that selective immunoproteasome inhibitors may be a promising strategy for stroke treatment.
Highlights
Immunoproteasome is a subtype of proteasome, which is predominantly present in the immune cells
Western blot showed that LMP2 changed in a time-dependent manner, namely, LMP2 increased as early as 4 h after reperfusion further increased at 24 h, peaked at 72 h and decreased at 7 days
Quantification analysis confirmed that the level of LMP2 protein changed from 4 h to 7 days in the ipsilateral ischemic cortex and striatum (*Po0.001, compared with the controls; #Po0.001 compared with the previous time point) (Figure 1B)
Summary
Immunoproteasome is a subtype of proteasome, which is predominantly present in the immune cells. Immunoproteasome contains two major catalytic subunits: LMP2 (low-molecular weight protein 2, PSMB9, β1i) and LMP7 (lowmolecular weight protein 7, PSMB8, β5i). It has been demonstrated that immunoproteasome has a critical role in regulating the production of proinflammatory cytokines[7] and maintaining protein homeostasis under cytokine-induced oxidative stress by preventing protein aggregate formation.[8,9] Blockage of LMP7 with immunoproteasome-specific. Immunoproteasome is present in neurons, astrocytes and endothelial cells in the brain areas such as the hippocampus and the cerebellum. The function of immunoproteasome in cerebral ischemia remains elusive. We investigated the time course and cellular distribution and function of immunoproteasome subunit LMP2 and LMP7 in the rat brain following cerebral ischemia-reperfusion
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