Abstract
Glucose-regulated protein (GRP78) or BiP, a 78-kDa chaperone protein located in the endoplasmic reticulum (ER), has recently been reported to be involved in the neuroglial response to ischemia-induced ER stress. The present study was designed to study the expression patterns of this protein and the cell types involved in the induction of GRP78 expression in rats treated with the mitochondrial toxin 3-nitropropionic acid (3-NP). GRP78 immunoreactivity was almost exclusively localized to striatal neurons in saline-treated controls, but GRP78 expression was induced in activated glial cells, including reactive astrocytes and activated microglia/macrophages, in the striata of rats treated with 3-NP. In the lesion core, increased GRP78 immunoreactivity was observed in the vasculature; this was evident in the lesion periphery of the core at 3 days after lesion induction, and was evenly distributed throughout the lesion core by 7 days after lesion induction. Vascular GRP78 expression was correlated, both temporally and spatially, with infiltration of activated microglia into the lesion core. In addition, this was coincident with the time and pattern of blood–brain barrier (BBB) leakage, detected by the extravasation of fluorescein isothiocyanate-albumin, an established BBB permeability marker. Vascular GRP78-positive cells in the lesion core were identified as endothelial cells, smooth muscle cells, and adventitial fibroblast-like cells, in which GRP78 protein was specifically localized to the cisternae of the rough ER and perinuclear cisternae, but not to other organelles such as mitochondria or nuclei. Thus, our data provide novel insights into the phenotypic and functional heterogeneity of GRP78-positive cells within the lesion core, suggesting the involvement of GRP78 in the activation/recruitment of activated microglia/macrophages and its potential role in BBB impairment in response to a 3-NP-mediated neurotoxic insult.
Highlights
The 78-kDa glucose-regulated protein (GRP78), known as the immunoglobulin heavy-chain binding protein or BiP, is a multifunctional regulator of endoplasmic reticulum (ER) homeostasis and stress response (Bole et al, 1989; Zhang and Zhang, 2010; Ouyang et al, 2011)
Three days after lesion induction, the lesion core, which was characterized by intense Fluoro-Jade B (FJB) staining, could be clearly divided into two areas according to the GRP78 expression profile: the epicenter and periphery of the lesion core (Figures 1D,E)
In a rat model of stroke, GRP78 expression is induced in activated glial cells, predominantly in brain macrophages and reactive astrocytes in the infarct and peri-infarct areas, respectively (Jin et al, 2018a)
Summary
The 78-kDa glucose-regulated protein (GRP78), known as the immunoglobulin heavy-chain binding protein or BiP, is a multifunctional regulator of endoplasmic reticulum (ER) homeostasis and stress response (Bole et al, 1989; Zhang and Zhang, 2010; Ouyang et al, 2011). GRP78 overexpression can have a neuroprotective effect by inhibiting the unfolded protein response, promoting autophagy, buffering calcium unbalance, and activating prosurvival signaling pathways (Ouyang et al, 2011; Zhang et al, 2015; Casas, 2017). Most studies investigating GRP78 have focused on neuron-specific functions, there is increasing evidence of alterations in GRP78 expression in activated glial cells after CNS insults. Our recent in vivo study showed prominent induction of GRP78 expression within activated glial cells after transient focal cerebral ischemia, predominantly in microglia/macrophages and reactive astrocytes (Jin et al, 2018a). The detailed expression pattern of GRP78 and the cell types involved in the induction of GRP78 expression have been analyzed only in the ischemic brain These findings need to be further substantiated in other models of CNS insults
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