P2X₇ nucleotide receptor: Modulation of LPS‐induced macrophage signaling and mediator production

Abstract

During infection or inflammation, high concentrations of extracellular nucleotides are released into the inflammatory microenvironment, supplying a source of ligand for purinergic receptors that are present on many immune cell types. The P2X 7 receptor, a member of the P2X purinergic receptor family of ATP-gated ion channels, is thought to play an important role in monocyte/macrophage activation. One factor that can powerfully activate macrophages is bacterial lipopolysaccharide (endotoxin, LPS) and although the mechanisms involved in this process are not well understood, it is clear that LPS activation of macrophages is central to the development of septic shock in response to Gram-negative bacteria. Several lines of evidence have demonstrated strong modulatory effects of adenine nucleotides on the events associated with LPS stimulation of macrophages. Further, because the signal transduction cascades initiated in macrophages upon LPS exposure are similar to those resulting from P2X 7 receptor stimulation, and because antagonism of the P2X 7 receptor can attenuate LPS-stimulated signaling events and mediator release, the P2X 7 receptor has been implicated in the control of macrophage responses to LPS. In addition, our laboratory has identified a consensus LPS-binding motif at the extreme carboxyl terminus of the P2X 7 receptor, further supporting the potential for a direct interaction between LPS and this purinergic receptor. In this review, we discuss potential regulatory domains and structural features of the P2X 7 receptor and outline some of the signal transduction pathways activated by P2X 7 receptor agonists. Moreover, we present evidence supporting a critical role for the P2X 7 receptor in modulating or mediating some of the biological effects of LPS in macrophages. Drug Dev. Res. 53:91-104, 2001.

Nucleotide receptor signaling in murine macrophages is linked to reactive oxygen species generation

“…The cation channel activity of P2X 7 mediates Na + and Ca 2+ influx and K + efflux, and several lines of evidence suggest that P2X 7 -induced alterations of intracellular Ca 2+ and K + levels are critical for bringing about many biological effects [1,3,4,8]. Moreover, prolonged activation of P2X 7 results in the formation of a non-specific pore that allows the passage of molecules up to 900 Da in size, and this activity has been proposed to contribute to the regulation of macrophage survival and inflammatory responses [1][2][3][4][5][6][7][8][9][10][11].…”

“…Thus, the events regulating MAP kinase cascades in activated macrophages are important for the understanding of inflammatory mediator production. In this regard, it is known that ERK1/ ERK2, p38, and JNK1/JNK2 are activated in response to P2X 7 agonists in a variety of cell types [8,[45][46][47][48]. Because P2X 7 action has been linked to inflammatory mediator production [8,49,50], it is likely that nucleotide-mediated MAP kinase activation modulates proinflammatory responses.…”

Mutation of a Dibasic Amino Acid Motif Within the C Terminus of the P2X7 Nucleotide Receptor Results in Trafficking Defects and Impaired Function

“…T he nucleotide receptor P2X 7 modulates multiple immune functions, including the production of inflammatory cytokines, PG, superoxide, and nitric oxide (1)(2)(3)(4)(5)(6). Additionally, several events requiring membrane fusion have been linked to P2X 7 , such as phagolysosomal maturation, giant cell formation, and the blebbing associated with microvesicle generation and IL-1␤ processing (7)(8)(9).…”

“…There are several lines of evidence demonstrating that P2X 7 expression is tightly regulated at the level of protein localization (2). Diverse cell types including PBMC, tissue macrophages, platelets, fibroblasts, neurons, and epithelial cells express P2X 7 mRNA.…”

Cell signaling via the P2X7 nucleotide receptor: linkage to ROS production, gene transcription, and receptor trafficking

“…In addition, many investigations have focused on the role of P2X 7 in the modulation of cellular responses to classical activators such as LPS, e.g., P2X 7 signaling in the classically activated macrophage has been shown to potentiate such diverse processes as the release of IL-1β, IL-6, and IL-18, the expression of iNOS, and the activation of metalloproteases and caspases (see [49][50][51] for reviews of P2X 7 signaling in immune cells).…”