P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways

Abstract

J. Neurochem. (2010) 114, 810–819. Abstract Microglia plays an important role in many neurodegenerative conditions. ATP leaked or released by damaged cells triggers microglial activation through P2 receptors, and stimulates the release of oxygen radicals, proinflammatory cytokines and chemokines from activated microglia. However, little is known about mechanisms underlying ATP‐induced chemokine release from microglia. In this study, we found that a high concentration of ATP induces the mRNA expression and release of CXCL2 from microglia. A similar effect was observed following treatment of microglia with a P2X7 receptor (P2X7R) agonist, 2′‐and 3′‐O‐(4‐benzoylbenzoyl) ATP, and this was inhibited by pre‐treatment with a P2X7R antagonist, Brilliant Blue G. ATP induced both activation of nuclear factor of activated T cells (NFAT) and MAPKs (p38, ERK, and JNK) through P2X7R. ATP‐induced mRNA expression of CXCL2 was inhibited by INCA‐6 (an NFAT inhibitor), SB203580 (a p38 inhibitor), U0126 (a MEK‐ERK inhibitor) and JNK inhibitor II (a JNK inhibitor). However, MAPK inhibitors did not inhibit activation of NFAT. In addition, protein kinase C inhibitors suppressed ATP‐induced ERK and JNK activation, and also inhibited ATP‐induced CXCL2 expression in microglia. These results suggest that ATP increased CXCL2 production via both NFAT and protein kinase C/MAPK signaling pathways through P2X7 receptor stimulation in microglia.

The Ectoenzyme E-NPP3 Negatively Regulates ATP-Dependent Chronic Allergic Responses by Basophils and Mast Cells

“…A previous study demonstrated that P2X7-mediated sensing of ATP induced the activation of several signal transduction pathways leading to the activation of microglia (Shiratori et al, 2010). In the present study, the involvement of ERK MAP kinases in the activation of basophils and mast cells was demonstrated.…”

“…Extracellular ATP activates ERK1 and/or ERK2 (ERK1/2) to induce cellular responses (Shiratori et al, 2010;Swanson et al, 1998). Therefore, we analyzed ATP-induced phosphorylation of ERK1/2 in basophils and mast cells ( Figure 6A).…”

Calcineurin and glial signaling: neuroinflammation and beyond

“…While it seems clear that CN is intimately involved in neuroinflammation, much work is still needed to fully assess the specific interactions between CN-dependent and -independent transcription factors, and how these interactions regulate specific inflammatory phenotypes. While this review has focused primarily on the role of CN in astrocytes, other work showing similar roles of CN in microglia [56-58,74] underscores the necessity to characterize the signaling properties of CN in other glial subtypes. Furthermore, the identification of other cellular targets of CN, including glutamate transporters, gap junctions, and BACE, suggests that CN’s impact on glial function may extend well beyond immune/inflammatory signaling.…”

Extracellular ATP and other nucleotides—ubiquitous triggers of intercellular messenger release

“…Both P2X7Rs and P2Y 6 Rs appeared to be involved [146]. In microglia, ATP induced messenger RNA (mRNA) expression and release of CCL2, CCL3, and CXCL2 mainly through activation of P2X7Rs [151][152][153]. Chemokine production was mediated via both calcineurindependent nuclear factor of activated T cells (NFAT) and PKC/MAPK signaling pathways.…”