Abstract:Background: Extracellular ATP is a powerful trigger of neuroinflammation by activating immune cells via P2X7 receptors. Acetylcholine and nicotinic agonists inhibit ATP-triggered proinflammatory cytokines via the so-called "cholinergic anti-inflammatory pathway" (CAP). However, it remains unclear as to what stage of ATP-induced signaling cholinergic agents provide this anti-inflammatory effect. Using the specific property of P2X7 receptor to open a pathway permeable to large molecules, associated with activati… Show more
“…Immune cells in the meninges are associated with the local meningeal lymphatic system [ 87 , 88 ] that provides a mechanism to clear metabolic waste from the brain and meninges themselves [ 89 ]. Consistent with the view that ATP, acting via P2X7 receptors, can trigger pro-inflammatory processes activating dural immune cells [ 27 , 83 , 84 ], we have observed that the P2X7-preferring agonist BzATP enhances release of the pro-inflammatory tumor necrosis factor-α (TNFα) and of the anti-inflammatory cytokine Il-10, both implicated in migraine pain [ 90 , 91 ]. Nevertheless, the release of these cytokines is similar in WT and KO mice lacking the meningeal lymphatic system [ 92 ].…”
Section: Introductionsupporting
confidence: 86%
“…2 ). Notably, these mast cells could serve both as the target for ATP acting via P2X7 receptors [ 27 , 83 , 84 ] and as an additional source of ATP release [ 85 ]. Fig.…”
Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.
“…Immune cells in the meninges are associated with the local meningeal lymphatic system [ 87 , 88 ] that provides a mechanism to clear metabolic waste from the brain and meninges themselves [ 89 ]. Consistent with the view that ATP, acting via P2X7 receptors, can trigger pro-inflammatory processes activating dural immune cells [ 27 , 83 , 84 ], we have observed that the P2X7-preferring agonist BzATP enhances release of the pro-inflammatory tumor necrosis factor-α (TNFα) and of the anti-inflammatory cytokine Il-10, both implicated in migraine pain [ 90 , 91 ]. Nevertheless, the release of these cytokines is similar in WT and KO mice lacking the meningeal lymphatic system [ 92 ].…”
Section: Introductionsupporting
confidence: 86%
“…2 ). Notably, these mast cells could serve both as the target for ATP acting via P2X7 receptors [ 27 , 83 , 84 ] and as an additional source of ATP release [ 85 ]. Fig.…”
Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.
“…3 A–F). Notably, the P2X7 receptor is also expressed in the dural mast cells 48 , 49 . Stimulation with 100 µM BzATP significantly increased the levels of IL-10 (treatment effect: p < 0.001) (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Extracellular ATP, acting primarily via P2X7 receptors, is a powerful trigger of inflammatory reactions involving different dural immune cells, including mast cells 48 , 49 , 73 , 74 . Consistent with this view, we found that the stimulation of meninges with the P2X7 agonist BzATP enhanced the release of the pro-inflammatory TNFα and Il-10, which are both implicated in migraine pathology 75 , 76 .…”
A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in ‘cleaning’ the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1–4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.
“…The P2X7R is abundantly expressed on macrophages and exhibits a variety of functions in innate and adaptive immune responses. Numerous studies reveal that the sequelae of P2X7R activation on macrophages includes the generation of membrane currents [ 47 , 48 ], membrane permeabilization, uptake of large molecules [ 49 ], massive perturbations of Na + , K + , and Ca 2+ homeostasis [ 24 , 50 ], inflammasome activation, and interleukin processing [ 51 , 52 , 53 ]. Cell membrane blebbing [ 47 , 54 ] and spontaneous cell fusion [ 55 ] of macrophages are also mediated by P2X7Rs.…”
Section: The Regulation Of Pore Formation On Macrophages Via P2x7rsmentioning
Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
