ATP-triggered unconventional secretion of GAPDH from macrophages: Its putative role as a modulator of inflammation

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme that is predominantly localized in the cytoplasm. However, emerging evidence indicates that GAPDH is secreted from mammalian cells and performs some of its biological functions in the extracellular space. In particular, it has been reported that high levels of GAPDH are secreted from macrophages that play important roles in the innate immune system. Despite these findings, since GAPDH is a leaderless protein, the mechanisms by which it reaches the extracellular environment remain unclear. In this regard, we have recently reported that extracellular ATP is able to trigger the secretion of GAPDH from mouse microglial cells, the resident macrophages in the brain. In addition, the activation of microglial cells by lipopolysaccharide (LPS) clearly facilitated ATP-induced GAPDH secretion. Importantly, exosome secretion mediated by the P2X7 receptor (P2X7R), an ATP-gated cation channel, was shown to play a critical role in the induction of unconventional GAPDH secretion from LPS-primed microglial cells. We also found that secreted GAPDH affects the LPS-induced phosphorylation of p38 mitogen-activated protein kinase in microglial cells. Furthermore, our preliminary data demonstrated that the ATP-induced secretion of GAPDH occurs in macrophage cell lines derived from other mouse peripheral tissues, such as the liver. Together, our findings suggest that GAPDH is generated extracellularly through the stimulation of activated macrophages by ATP, and the secreted GAPDH acts as a mediator of macrophage-related inflammation in an autocrine/paracrine fashion.