In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1β in the murine brain

Abstract

The P2X 7 receptor (P2X 7 R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X 7 R has a role in the release of biologically active proinflammatory cytokines such as IL-1β, IL-6 and TNFα. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X 7 R −/− mice produce less IL-1β compared to glial cells from brains of wild-type mice. This is not the case for TNFα and IL-6. Our results indicate a selective effect of the P2X7R gene deletion on release of IL-1β release but not of IL-6 and TNFα. In addition, we confirm that only microglial cells produce IL-1β, and this release is dependent on P2X 7 R and ABC1 transporter. Because IL-1β is a key regulator of the brain cytokine network and P2X 7 R is an absolute requirement for IL-1β release, we further investigated whether response of brain cytokines to LPS in vivo was altered in P2X 7 R −/− mice compared to wild-type mice. IL-1β and TNFα mRNAs were less elevated in the brain of P2X 7 R −/− than in the brain of wild-type mice in response to systemic LPS. These results show that P2X7R plays a key role in the brain cytokine response to immune stimuli, which certainly applies also to cytokinedependent alterations in brain functions including sickness behavior.

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…However, it appears that the scenario is more complex as only LPS-induced, but not the basal IL-1b levels are subject to regulation by P2X7 receptors in the rodent brain (Csolle and Sperlagh, 2010;Mingam et al, 2008) and the mood stabilizing phenotype detected in the absence of P2X7 receptors was not transferred with bone marrow transplantation (Csolle et al, 2013b). The contribution of P2X7 receptors present on cells of hematopoietic origin such as peripheral immune cells to behavioral changes detected in naïve animals, therefore, seems minimal.…”

Microglia Proliferation Is Controlled by P2X7 Receptors in a Pannexin-1-Independent Manner during Early Embryonic Spinal Cord Invasion

“…While P2X7R, in addition to P2X4R and P2X1R, is also expressed by embryonic microglia (Xiang and Burnstock, 2005), its functions remain unknown at these developmental stages. In the adult, P2X7R is involved, in addition to microglia activation and proliferation, in a variety of important effector functions of microglia (Kettenmann et al, 2011), including the release of interleukin (IL)-1␤, IL-1␣, and TNF-␣ (Ferrari et al, 1997;Hide et al, 2000;Brough et al, 2002;Mingam et al, 2008). A remarkable feature of P2X7R is that it promotes the formation of a large pore permeable to hydrophilic moieties up to 900 Da (Surprenant et al, 1996), which has been proposed to evoke IL-1␤ release, to mediate P2X7R effects on the Descartes, France) and by Micaela Galante (IBBMC, CNRS UMR 8619, France).…”

Astroglial P2X7 receptor current density increased following long-term exposure to rotenone

“…In addition, we compared the inactivation speed of P2X7 receptors in different groups and found that long-term treatment with rotenone not only increased current density, but also extended channel inactivation time. P2X7 receptors play a regulatory role in the secretion of many cytokines [24]. For example, activation of P2X7 receptors in astrocytes inhibits TNF-α secretion [8].…”