Abstract
The 78-kDa glucose-regulated protein (Grp78) is stress-inducible chaperone that mostly reside in the endoplasmic reticulum. Grp78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. As antigen-presenting cells (APCs) play a critical role in both the priming of adaptive immune responses and the induction of self-tolerance, herein, we investigated the effect of Grp78 on the maturation of murine myeloid APCs (CD11c+ cells). Results showed that CD11c+ cells could be bound by AF488-labeled Grp78 and that Grp78 treatment induced a tolerogenic phenotype comparable to immature cells. Furthermore, when exposed to lipopolysaccharide, Grp78-treated CD11c+ cells (DCGrp78) did not adopt a mature dendritic cell phenotype. DCGrp78-primed T cells exhibited reduced proliferation along with a concomitant expansion of CD4+CD25+FoxP3+ cells in pancreaticoduodenal lymph nodes and induction of T cell apoptosis in vitro and ex vivo. The above work suggests that Grp78 is an immunomodulatory molecule that could aid resolution of inflammation. It may thus contribute to induce durable tolerance to be of potential therapeutic benefit in transplanted allogeneic grafts and autoimmune diseases such as type I diabetes.
Highlights
The endoplasmic reticulum (ER) chaperone Grp78/BiP is a central regulator of ER homeostasis, and its upregulation is widely used as a sentinel marker under pathologic conditions for ER stress, such as hypoxia, hypoglycemia, infection, nutrient deprivation, low-calcium, and others [1, 2]
We previously reported that recombinant mouse Grp78 could program splenic B cells into CD19hiFasL+/ PD-L1+ IL-10-producing B cells to suppress T cell proliferation [17]
To assess the effect of Grp78 on modulation of CD11c+ cells, cells were cultured in the presence of Grp78 for 7 days and subjected to phenotype analysis
Summary
The endoplasmic reticulum (ER) chaperone Grp78/BiP is a central regulator of ER homeostasis, and its upregulation is widely used as a sentinel marker under pathologic conditions for ER stress, such as hypoxia, hypoglycemia, infection, nutrient deprivation, low-calcium, and others [1, 2]. Upregulation of Grp could lead to the translocation of Grp to other cellular locations and secretion of Grp into the extracellular compartment [7,8,9,10,11]. Our previous work confirmed that overexpression of Grp in insulinoma cells prolonged cell survival and subsequently maintained normoglycemia in diabetic Balb/c mice [12, 13]. In the following experiments, it was found that Grp78-overexpressing insulinoma cell-treated animals secreted high levels of IL-4, suggesting the immunosuppressive ability of Grp in beta cell transplantation [13]. It was not clear how Grp exerted such immunomodulatory effect for improvement of alloimmunity
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