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      Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1β via Different Combinations of Nicotinic Acetylcholine Receptor Subunits α7, α9 and α10

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          Abstract

          Recently, we discovered a cholinergic mechanism that inhibits the adenosine triphosphate (ATP)-dependent release of interleukin-1β (IL-1β) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of α7, α9 and/or α10 subunits. Furthermore, we identified phosphocholine (PC) and dipalmitoylphosphatidylcholine (DPPC) as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, PC does not provoke ion channel responses at conventional nAChRs composed of subunits α9 and α10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine (LPC) and glycerophosphocholine (G-PC), function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice, we demonstrated that inhibition of ATP-dependent release of IL-1β by acetylcholine (ACh), nicotine and PC depends on subunits α7, α9 and α10. Using a panel of nAChR antagonists and siRNA technology, we confirmed the involvement of these subunits in the control of IL-1β release in the human monocytic cell line U937. Furthermore, we showed that LPC (C16:0) and G-PC efficiently inhibit ATP-dependent release of IL-1β. Of note, the inhibitory effects mediated by LPC and G-PC depend on nAChR subunits α9 and α10, but only to a small degree on α7. In Xenopus laevis oocytes heterologously expressing different combinations of human α7, α9 or α10 subunits, ACh induced canonical ion channel activity, whereas LPC, G-PC and PC did not. In conclusion, we demonstrate that canonical nicotinic agonists and PC elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits α7, α9 and α10. For the metabotropic signaling of LPC and G-PC, nAChR subunits α9 and α10 are needed, whereas α7 is virtually dispensable. Furthermore, molecules bearing a PC group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR.

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          The inflammasome: an integrated view.

          An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1β (IL-1β). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1β necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1β. This event renders the cell competent for NLRP3 inflammasome activation and IL-1β secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions. © 2011 John Wiley & Sons A/S.
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            Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives

            The inflammasome is a molecular platform formed by activation of an innate immune pattern recognition receptor seed, such as NLRP3. Once activated, NLRP3 recruits the adapter ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), which in turn recruits procaspase-1. Procaspase-1 autocatalyzes its cleavage and activation, resulting in maturation of the precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines and initiation of pyroptotic cell death. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of diseases, including genetically inherited autoinflammatory conditions as well as chronic diseases in which NLRP3 is abnormally activated. The NLRP3 inflammasome has been linked to diseases such as Alzheimer’s disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration. In this review, we describe the NLRP3 inflammasome complex and its activation in disease, and detail the current therapies that modulate either the NLRP3 inflammasome complex itself or the two cytokines it is responsible for activating, ie, IL-1β and IL-18.
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              Extracellular ATP in the immune system: more than just a "danger signal".

              Extracellular adenosine 5'-triphosphate (eATP) is ubiquitously used for cell-to-cell communication. The low concentration of eATP ([eATP]) that exists in a "halo" surrounding resting cells signals the presence of neighboring living cells. Transient increases in [eATP] are used for basic physiological signaling, namely, in the nervous and vascular systems. Larger increases in [eATP] that are associated with cell death serve as a key "danger" signal in inflammatory processes. Two studies now point to roles for ATP in the immune system: providing a costimulatory signal to T cells and driving the differentiation of intestinal T helper 17 (T(H)17) cells.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                05 July 2017
                2017
                : 11
                : 189
                Affiliations
                [1] 1Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen Giessen, Germany
                [2] 2Institute of Anatomy and Cell Biology, Justus-Liebig-University Giessen Giessen, Germany
                [3] 3Institute of Anatomy and Cell Biology, Saarland University Homburg, Germany
                [4] 4Member of the German Centre for Lung Research Giessen, Germany
                [5] 5Institute of Animal Physiology, Justus-Liebig-University Giessen Giessen, Germany
                [6] 6School of Biology, Newcastle University Newcastle upon Tyne, United Kingdom
                [7] 7Department of Biology, University of Utah Salt Lake City, UT, United States
                [8] 8George E. Wahlen Veterans Affairs Medical Center Salt Lake City, UT, United States
                [9] 9Department of Psychiatry, University of Utah Salt Lake City, UT, United States
                Author notes

                Edited by: Barbara Jane Morley, Boys Town National Research Hospital, United States

                Reviewed by: Richard J. Lewis, The University of Queensland, Australia; Koichiro Kawashima, Kitasato University, Japan

                These authors have contributed equally to this work.

                Article
                10.3389/fncel.2017.00189
                5496965
                28725182
                d8efbd36-1321-463e-82a4-451bc9a3fcb4
                Copyright © 2017 Zakrzewicz, Richter, Agné, Wilker, Siebers, Fink, Krasteva-Christ, Althaus, Padberg, Hone, McIntosh and Grau.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 April 2017
                : 20 June 2017
                Page count
                Figures: 10, Tables: 1, Equations: 0, References: 69, Pages: 16, Words: 11497
                Funding
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: GR 1094/7-1, SFB TR84
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: P01-GM48677, R01-GM103801
                Funded by: Hessisches Ministerium für Wissenschaft und Kunst 10.13039/501100003495
                Award ID: Non-neuronal cholinergic systems
                Categories
                Neuroscience
                Original Research

                Neurosciences
                acetylcholine,chrna,glycerophosphocholine,inflammasome,interleukin-1beta,lysophosphatidylcholine,nicotine and phosphocholine

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