Abstract
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.
Highlights
International Collaborative Centre on Big Science Plan for Purinergic Signalling, Chengdu University of TCM, School of Acupunct3ure and Tuina, Chengdu University of TCM, Chengdu 610075, China
This review focuses on the state of our present knowledge about P2X7Rs in macrophages during inflammatory processes, and discusses the possibility of P2X7Rs as therapeutic targets to alleviate the deleterious consequences of macrophage activation
Multiple studies indicate that the activation of P2X7Rs in macrophages is involved in peripheral inflammatory diseases, including rheumatoid arthritis [53], Crohn’s disease [108], liver fibrosis [109,110], sepsis [101,111], renal inflammation [112,113], and pulmonary inflammation [114]
Summary
While millimolar concentrations of ATP are stored in the cell interior, where they are used under anaerobic conditions as an energy supply, this nucleotide can escape to the extracellular space through discontinuities generated by metabolic/mechanical damage to the cell membrane or by means of membrane transporters and channels. Extracellular ATP or its enzymatic breakdown products, ADP, AMP and adenosine (see below), may stimulate a range of membrane receptors (Rs) [3]. These receptors are classified as belonging to two types termed P2 and. Whereas P2XRs respond only to ATP, P2YRs respond to ATP/ADP, UTP/UDP, or UDPadenosine and eventually to the inactive inosine within the extracellular space by the glucose. The four major groups of ecto-nucleotidases are adenosine and eventually to the inactive inosine within the extracellular by the ecto-nucleoside triphosphate diphosphohydrolases (NPTDases), space ecto-5’-nucleotidase, activity of ecto-nucleotidases [9,10]. P2X7R is widely distributed and functional at the innate cells of the adaptive immune stituting the first line of defense against invading pathogens. This review focuses on the state of our present knowledge about P2X7Rs in macrophages during inflammatory processes, and discusses the possibility of P2X7Rs as therapeutic targets to alleviate the deleterious consequences of macrophage activation
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