{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:28:47Z","timestamp":1789522127570,"version":"build-2803163510"},"reference-count":130,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Frequent diseases of the CNS, such as Alzheimer\u2019s disease, Parkinson\u2019s disease, multiple sclerosis, and psychiatric disorders (e.g., schizophrenia), elicit a neuroinflammatory response that contributes to the neurodegenerative disease process itself. The immune and nervous systems use the same mediators, receptors, and cells to regulate the immune and nervous systems as well as neuro-immune interactions. In various neurodegenerative diseases, peripheral inflammatory mediators and infiltrating immune cells from the periphery cause exacerbation to current injury in the brain. Acetylcholine (ACh) plays a crucial role in the peripheral and central nervous systems, in fact, other than cells of the CNS, the peripheral immune cells also possess a cholinergic system. The findings on peripheral cholinergic signaling, and the activation of the \u201ccholinergic anti-inflammatory pathway\u201d mediated by ACh binding to \u03b17 nAChR as one of the possible mechanisms for controlling inflammation, have restarted interest in cholinergic-mediated pathological processes and in the new potential therapeutic target for neuro-inflammatory-degenerative diseases. Herein, we focus on recent progress in the modulatory mechanisms of the cholinergic anti-inflammatory pathway in neuroinflammatory diseases.<\/jats:p>","DOI":"10.3390\/diseases9020029","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T21:47:33Z","timestamp":1618264053000},"page":"29","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Cholinergic Modulation of the Immune System in Neuroinflammatory Diseases"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4164-8781","authenticated-orcid":false,"given":"Marcella","family":"Reale","sequence":"first","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, University \u201cG.d\u2019Annunzio\u201d, 65122 Chieti-Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-4226","authenticated-orcid":false,"given":"Erica","family":"Costantini","sequence":"additional","affiliation":[{"name":"Department of Medical, Oral and Biotechnological Science, University \u201cG.d\u2019Annunzio\u201d, 65122 Chieti-Pescara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Iversen, L.L., Iversen, S.D., Bloom, F.E., and Roth, R.H. (2009). Acetylcholine. Introduction to Neuropsychopharmacology, Oxford University Press.","DOI":"10.1093\/med\/9780195380538.001.0001"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1023\/A:1022809003997","article-title":"High-affinity choline transporter","volume":"28","author":"Okuda","year":"2003","journal-title":"Neurochem. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrn1035","article-title":"Neurobiology of butyrylcholinesterase","volume":"42","author":"Darvesh","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/35067589","article-title":"Acetylcholinesterase--new roles for an old actor","volume":"24","author":"Soreq","year":"2001","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.2174\/138161206778522056","article-title":"Muscarinic acetylcholine receptors","volume":"12","author":"Ishii","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.pneurobio.2004.09.006","article-title":"Neuronal nicotinic receptors: From structure to pathology","volume":"74","author":"Gotti","year":"2004","journal-title":"Prog. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/35013070","article-title":"Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin","volume":"405","author":"Borovikova","year":"2000","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2008.11.053","article-title":"Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: Central role for JAK2 activation of STAT3 and NF-kappaB","volume":"1256","author":"Marrero","year":"2009","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s11062-011-9203-7","article-title":"Possible Effect of Activation of \u03b17-Nicotinic Acetylcholine Receptors in the Mitochondrial Membrane on the Development of Apoptosis","volume":"43","author":"Gergalova","year":"2011","journal-title":"Neurophysiology"},{"key":"ref_10","first-page":"e1290","article-title":"Nicotinic acetylcholine receptors in mitochondria: Subunit composition, function and signalling","volume":"3","author":"Skok","year":"2016","journal-title":"Neurotransmitter"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.intimp.2015.04.007","article-title":"Inflammation decreases the level of alpha7 nicotinic acetylcholine receptors in the brain mitochondria and makes them more susceptible to apoptosis induction","volume":"29","author":"Lykhmus","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"350","DOI":"10.2119\/molmed.2013.00117","article-title":"\u03b17 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release","volume":"20","author":"Lu","year":"2014","journal-title":"Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0163-7258(99)00071-6","article-title":"Extraneuronal cholinergic system in lymphocytes","volume":"861","author":"Kawashima","year":"2000","journal-title":"Pharmacol. Ther."},{"key":"ref_14","first-page":"251","article-title":"Presence of acetylcholine in human blood and its localization in circulating mononuclear leukocytes","volume":"9","author":"Kawashima","year":"1993","journal-title":"Biog. Amines"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/0304-3940(95)12180-3","article-title":"Species differences in the concentration of acetylcholine, a neurotransmitter, in whole blood and plasma","volume":"201","author":"Fujii","year":"1995","journal-title":"Neurosci. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1073\/pnas.71.4.1330","article-title":"Cholinergic augmentation of lymphocyte-mediated cytotoxicity. A study of the cholinergic receptor of cytotoxic T lymphocytes","volume":"74","author":"Strom","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1016\/0024-3205(87)90705-3","article-title":"Molecular form of human lymphocyte membrane-bound acetylcholineesterase","volume":"41","author":"Bartha","year":"1987","journal-title":"Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1365-2141.1982.tb01914.x","article-title":"Acetylcholinesterase activity of lymphocytes: An enzyme characteristic of T-cells","volume":"50","author":"Bartha","year":"1982","journal-title":"Br. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0165-5728(02)00325-9","article-title":"Immunochemical and immuno cyto chemical characterization of cholinergic markers in human peripheral blood lymphocytes","volume":"132","author":"Tayebati","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jphs.2017.05.002","article-title":"Physiological functions of the cholinergic system in immune cells","volume":"134","author":"Fujii","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0304-3940(99)00259-1","article-title":"Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines","volume":"266","author":"Sato","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1016\/j.lfs.2007.02.005","article-title":"The role of nicotinic receptors in B-lymphocyte development and activation","volume":"80","author":"Skok","year":"2007","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0165-5728(97)00155-0","article-title":"Rat lympocytes produce and secrete acetylcholine in dependence of differentiation and activation","volume":"81","author":"Rinner","year":"1998","journal-title":"J. Neuroimmunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.4049\/jimmunol.1002711","article-title":"Cytokine-induced alterations of alpha7 nicotinic receptor in colonic CD4 T cells mediate dichotomous response to nicotine in murine models of Th1\/Th17- versus Th2-mediated colitis","volume":"187","author":"Galitovskiy","year":"2011","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jneuroim.2013.12.003","article-title":"SLURP-1, an endogenous alpha7 nicotinic acetylcholine receptor allosteric ligand, is expressed in CD205(+) dendritic cells in human tonsils and potentiates lymphocytic cholinergic activity","volume":"267","author":"Fujii","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit","volume":"334","author":"Olofsson","year":"2011","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1038\/ni1229","article-title":"Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway","volume":"6","author":"The","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1600-065X.2012.01138.x","article-title":"Rethinking inflammation: Neural circuits in the regulation of immunity","volume":"248","author":"Olofsson","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13874","DOI":"10.1074\/jbc.RA118.003443","article-title":"Interaction of the a7-nicotinic subunit with its human-specific duplicated dupa7 isoform in mammalian cells: Relevance in human inflammatory responses","volume":"293","author":"Maldifassi","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.intimp.2009.12.001","article-title":"Auto\/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors","volume":"10","author":"Chernyavsky","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1073\/pnas.69.10.2995","article-title":"Alteration of the cytotoxic action of sensitized lymphocytes by cholinergic agents and activators of adenylate cyclase","volume":"69","author":"Strom","year":"1972","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1046\/j.1365-2567.2003.01655.x","article-title":"Evidence for the immunosuppressive role of nicotine on human dendritic cell functions","volume":"109","author":"Guinet","year":"2003","journal-title":"Immunology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/glia.20467","article-title":"Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration","volume":"555","author":"Qin","year":"2007","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8546","DOI":"10.1523\/JNEUROSCI.5002-13.2014","article-title":"Neurodegeneration by activation of the microglial complement-phagosome pathway","volume":"3425","author":"Bodea","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_35","first-page":"1711","article-title":"Chronic peripheral inflammation: A possible contributor to neurodegenerative diseases","volume":"169","author":"Lana","year":"2021","journal-title":"Neural. Regen. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sandhu, J.K., and Kulka, M. (2021). Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int. J. Mol. Sci., 223.","DOI":"10.3390\/ijms22031093"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.3389\/fphar.2019.01008","article-title":"Neuroinflammation as a Common Feature of Neurodegenerative Disorders","volume":"10","author":"Maccioni","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1042\/BST0351127","article-title":"Chronic microglial activation and progressive dopaminergic neurotoxicity","volume":"35","author":"Block","year":"2007","journal-title":"Biochem. Soc. Trans."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3389\/fncel.2018.00488","article-title":"Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response","volume":"12","author":"Bachiller","year":"2018","journal-title":"Front. Cell Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00401-019-01980-7","article-title":"The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis","volume":"137","author":"Brambilla","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/eji.201444823","article-title":"Cerebral regulatory T cells restrain microglia\/macrophage-mediated inflammatory responses via IL-10","volume":"45","author":"Xie","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/nn.4610","article-title":"High-dimensional, single-cell characterization of the brain\u2019s immune compartment","volume":"20","author":"Korin","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1126\/science.aag2638","article-title":"Multifaceted interactions between adaptive immunity and the central nervous system","volume":"353","author":"Kipnis","year":"2016","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.molmed.2011.05.012","article-title":"Regulatory T cells in CNS injury: The simple, the complex and the confused","volume":"17","author":"Walsh","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/nn1629","article-title":"Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood","volume":"9","author":"Ziv","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.bbi.2013.08.013","article-title":"Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire","volume":"35","author":"Radjavi","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"916","DOI":"10.3389\/fnins.2019.00916","article-title":"Role of the Immune System in the Development of the Central Nervous System","volume":"13","author":"Morimoto","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0166-2236(02)02154-9","article-title":"Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases","volume":"25","author":"Neumann","year":"2002","journal-title":"Trends Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-2009-1015","article-title":"Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer\u2019s disease","volume":"17","author":"Larbi","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s12035-008-8026-z","article-title":"Immune-to-brain signaling: How important are the blood-brain barrier-independent pathways?","volume":"372","author":"Quan","year":"2008","journal-title":"Mol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.bbi.2004.01.004","article-title":"The influence of systemic inflammation on inflammation in the brain: Implications for chronic neurodegenerative disease","volume":"18","author":"Perry","year":"2004","journal-title":"Brain Behav. Immun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nri2015","article-title":"Systemic infections and inflammation affect chronic neurodegeneration","volume":"7","author":"Perry","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"582825","DOI":"10.3389\/fimmu.2020.582825","article-title":"Role of Peripheral Immune Cells-Mediated Inflammation on the Process of Neurodegenerative Diseases","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.biopsych.2008.07.024","article-title":"Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease","volume":"65","author":"Cunningham","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nn.4475","article-title":"The role of peripheral immune cells in the CNS in steady state and disease","volume":"20","author":"Prinz","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41583-019-0201-x","article-title":"Macrophages at CNS interfaces: Ontogeny and function in health and disease","volume":"20","author":"Kierdorf","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/nm1651","article-title":"Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation","volume":"13","author":"Kebir","year":"2007","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/187152410790780154","article-title":"Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands","volume":"10","author":"Pacheco","year":"2010","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1016\/j.lfs.2007.01.002","article-title":"Neuro-immune interactions via the cholinergic anti-inflammatory pathway","volume":"80","author":"Pavlov","year":"2007","journal-title":"Life Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/nm1124","article-title":"Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis","volume":"10","author":"Wang","year":"2004","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/j.1750-3639.2007.00064.x","article-title":"The immunopathology of multiple sclerosis: An overview","volume":"17","author":"Lassmann","year":"2007","journal-title":"Brain Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrn3275","article-title":"Will the real multiple sclerosis please stand up?","volume":"13","author":"Stys","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ncpneuro0154","article-title":"Immunopathogenesis and immunotherapy of multiple sclerosis","volume":"2","author":"Hemmer","year":"2006","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jneuroim.2013.06.007","article-title":"Biased Treg\/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple sclerosis and its correlation with severity of symptoms","volume":"2621","author":"Jamshidian","year":"2013","journal-title":"J. Neuroimmunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.bbi.2010.01.014","article-title":"Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis","volume":"24","author":"Murphy","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107391","DOI":"10.1016\/j.intimp.2021.107391","article-title":"Cholinergic modulation of the immune syste -A novel therapeutic target for myocardial inflammation","volume":"93","author":"Lu","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.expneurol.2010.09.020","article-title":"Attenuation of CNS inflammatory responses by nicotine involves \u03b17 and non-\u03b17 nicotinic receptors","volume":"227","author":"Hao","year":"2011","journal-title":"Exp. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1124\/jpet.110.169961","article-title":"Stimulation of \u03b17 nicotinic acetylcholine receptor by nicotine increases suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro","volume":"335","author":"Wang","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.lfs.2009.07.010","article-title":"Alpha 7nicotinic acetylcholine receptor modulates lymphocyte activation","volume":"85","author":"Dionisio","year":"2009","journal-title":"Life Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6681","DOI":"10.4049\/jimmunol.0902212","article-title":"Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses","volume":"183","author":"Nizri","year":"2009","journal-title":"J. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic acetylcholine receptor alpha7 subunit is anessential regulator of inflammation","volume":"421","author":"Wang","year":"2003","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2119\/2008-00079.Parrish","article-title":"Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptormediated signaling","volume":"14","author":"Parrish","year":"2008","journal-title":"Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1084\/jem.20040463","article-title":"Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation","volume":"201","author":"Saeed","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1177\/09680519030090060401","article-title":"Neural inhibition of inflammation: The cholinergic anti-inflammatory pathway","volume":"9","author":"Czura","year":"2003","journal-title":"J. Endotoxin Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/j.1365-2249.2006.03169.x","article-title":"Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7","volume":"146","author":"Yoshikawa","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2119\/molmed.2009.00039","article-title":"The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE","volume":"15","author":"Goldstein","year":"2009","journal-title":"Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"12656","DOI":"10.3390\/ijms131012656","article-title":"Relation between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis patients","volume":"1310","author":"Reale","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"667","DOI":"10.3109\/08820139.2014.914532","article-title":"Activation of \u03b17nAChR by nicotine reduced the Th17 response in (CD4+)T lymphocytes","volume":"437","author":"Liu","year":"2014","journal-title":"Immunol. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Di Bari, M., Reale, M., Di Nicola, M., Orlando, V., Galizia, S., Porfilio, I., Costantini, E., D\u2019Angelo, C., Ruggieri, S., and Biagioni, S. (2016). Dysregulated homeostasis of acetylcholine levels in immune cells of RR-multiple sclerosis patients. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122009"},{"key":"ref_80","first-page":"109","article-title":"Cholinergic system and neuroinflammation: Implication in multiple sclerosis","volume":"17","author":"Reale","year":"2017","journal-title":"CNS Agents Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Gatta, V., Mengod, G., Reale, M., and Tata, A.M. (2020). Possible Correlation between Cholinergic System Alterations and Neuro\/Inflammation in Multiple Sclerosis. Biomedicines, 86.","DOI":"10.3390\/biomedicines8060153"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"E6202","DOI":"10.1073\/pnas.1705491114","article-title":"Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes\/ macrophages","volume":"114","author":"Jiang","year":"2017","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.bcp.2014.01.009","article-title":"The complexities of the pathology\u2013pathogenesis relationship in Alzheimer disease","volume":"88","author":"Castellani","year":"2014","journal-title":"Biochemical. Pharmacol."},{"key":"ref_84","first-page":"10447","article-title":"A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation","volume":"4035","author":"Canales","year":"2001","journal-title":"Biochemistry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0006-8993(02)03262-6","article-title":"Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein","volume":"953","author":"Apelt","year":"2002","journal-title":"Brain Res."},{"key":"ref_86","first-page":"a006346","article-title":"Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature","volume":"21","author":"Rogers","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3233\/JAD-170999","article-title":"Expression Profiling of Cytokine, Cholinergic Markers, and Amyloid-\u03b2 Deposition in the APPSWE\/PS1dE9 Mouse Model of Alzheimer\u2019s Disease Pathology","volume":"621","author":"Reale","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1212\/WNL.0b013e3181b6bb95","article-title":"Systemic inflammation and disease progression in Alzheimer disease","volume":"73","author":"Holmes","year":"2009","journal-title":"Neurology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jneuroim.2015.04.014","article-title":"The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer\u2019s disease, mild cognitive impairment or Parkinson\u2019s disease","volume":"283","author":"Dursun","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"447","DOI":"10.2174\/156720512800492549","article-title":"Relationship between Inflammatory Mediators, A\u03b2 Levels and ApoE Genotype in Alzheimer Disease","volume":"9","author":"Reale","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.bbi.2016.02.009","article-title":"T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer\u2019s disease-like cerebral amyloidosis","volume":"54","author":"Ferretti","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.bbi.2010.01.003","article-title":"Activation of mixed glia by Abeta-specific Th1 and Th17 cells and its regulation by Th2 cells","volume":"24","author":"McQuillan","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.neuropharm.2005.11.006","article-title":"The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer\u2019s diseasepatients","volume":"505","author":"Reale","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"608","DOI":"10.2174\/1567205010666131212113218","article-title":"Selective Acetyl- and Butyrylcholinesterase Inhibitors Reduce Amyloid-b Ex Vivo Activation of Peripheral Chemo-cytokines From Alzheimer\u2019s Disease Subjects: Exploring the Cholinergic Anti-inflammatory Pathway","volume":"11","author":"Reale","year":"2014","journal-title":"Curr. Alzheimer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nri3705","article-title":"Innate immune activation in neurodegenerative disease","volume":"14","author":"Heneka","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fnagi.2020.00068","article-title":"Nuclear Factor-\u03baB Dysregulation and \u03b1-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson\u2019s Disease","volume":"12","author":"Bellucci","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_97","first-page":"337","article-title":"Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line","volume":"694","author":"Couch","year":"2011","journal-title":"Neurosci. Res."},{"key":"ref_98","first-page":"182","article-title":"Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease","volume":"1191","author":"Brochard","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbi.2008.07.003","article-title":"Peripheral cytokines profile in Parkinson\u2019s disease","volume":"231","author":"Reale","year":"2009","journal-title":"Brain Behav. Immun."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Harms, A.S., Ferreira, S.A., and Romero-Ramos, M. (2021). Periphery and brain, innate and adaptive immunity in Parkinson\u2019s disease. Acta Neuropathol.","DOI":"10.1007\/s00401-021-02268-5"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/nature05292","article-title":"Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases","volume":"443","author":"Lin","year":"2006","journal-title":"Nature."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e101064","DOI":"10.15252\/embj.2018101064","article-title":"Systemic inflammation impairs microglial A\u03b2 clearance through NLRP3 inflammasome","volume":"38","author":"Tejera","year":"2019","journal-title":"EMBO J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1002\/eji.201040540","article-title":"Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis","volume":"40","author":"Cai","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1089\/ars.2010.3555","article-title":"Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine attenuates inflammatory response in macrophages and improves survival in experimental model of sepsis through heme oxygenase-1 induction","volume":"14","author":"Tsoyi","year":"2011","journal-title":"Antioxid Redox Signal."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.3389\/fimmu.2017.01489","article-title":"The Cholinergic System Modulates Memory and Hippocampal Plasticity via Its Interactions with Non-Neuronal Cells","volume":"8","author":"Maurer","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev-immunol-020711-075013","article-title":"microRNA regulation of inflammatory responses","volume":"30","author":"Rao","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1161\/ATVBAHA.112.300068","article-title":"MicroRNAs in immune response and macrophage polarization","volume":"33","author":"Liu","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2174\/1871523011312020005","article-title":"MicroRNA: Novel modulators of the cholinergic anti-inflammatory pathway","volume":"12","author":"Priyadarshini","year":"2013","journal-title":"Antiinflamm. Antiallergy Agents Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fnmol.2014.00009","article-title":"Predicted overlapping microRNA regulators of acetylcholine packaging and degradation in neuroinflammation-related disorders","volume":"7","author":"Nadorp","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.cbi.2012.07.007","article-title":"Cholinergic involvement and manipulation approaches in multiple system disorders","volume":"203","author":"Ofek","year":"2013","journal-title":"Chem. Biol. Interact."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nm.2266","article-title":"MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C\/EBP-\u03b1-PU.1 pathway","volume":"17","author":"Ponomarev","year":"2011","journal-title":"Nat. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/cr.2013.116","article-title":"MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines","volume":"23","author":"Sun","year":"2013","journal-title":"Cell Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"312","DOI":"10.3892\/ijmm.2016.2613","article-title":"MicroRNA-2055b inhibits HMGB1 expression in LPS-induced sepsis","volume":"38","author":"Zhou","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1002\/eji.201343486","article-title":"MicroRNA-132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti-inflammation: A new Ahr-based exploration","volume":"43","author":"Hanieh","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Jasiecki, J., and Wasag, B. (2019). Butyrylcholinesterase Protein Ends in the Pathogenesis of Alzheimer\u2019s Disease-CouldBCHE Genotyping Be Helpful in Alzheimer\u2019s Therapy. Biomolecules, 9.","DOI":"10.3390\/biom9100592"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5223","DOI":"10.1038\/s41598-019-41578-3","article-title":"Synergy between the alteration in the N-terminal region of butyrylcholinesterase K variant and apolipoprotein E4 in late-onsetAlzheimer\u2019s disease","volume":"9","author":"Jasiecki","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/s41598-018-19701-7","article-title":"Butyrylcholinesterase and Acetylcholinesterase polymorphisms in Multiple Sclerosis patients: Implication in peripheral inflammation","volume":"8","author":"Reale","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1524107","DOI":"10.1155\/2017\/1524107","article-title":"Serum Butyrylcholinesterase Activity: A Biomarker for Parkinson\u2019s Disease and Related Dementia","volume":"2017","author":"Dong","year":"2017","journal-title":"BioMed. Res. Int."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1111\/jnc.13928","article-title":"Personalized genetics of the cholinergic blockade of neuroinflammation","volume":"142","author":"Simchovitz","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4569","DOI":"10.1093\/hmg\/ddu170","article-title":"Competing targets of microRNA-608 affect anxiety and hypertension","volume":"23","author":"Hanin","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1038\/onc.2012.318","article-title":"MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R","volume":"32","author":"Gong","year":"2013","journal-title":"Oncogene"},{"key":"ref_122","first-page":"1179","article-title":"Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer\u2019s Disease","volume":"8","author":"Russo","year":"2017","journal-title":"Curr. Drug Targets"},{"key":"ref_123","first-page":"196","article-title":"Polymorphisms in the Cholinergic Receptors Muscarinic (CHRM2 and CHRM3) Genes and Alzheimer\u2019s Disease","volume":"10","author":"Chee","year":"2018","journal-title":"J. Med. Biotechnol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1016\/j.neurobiolaging.2005.08.024","article-title":"Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer\u2019s disease","volume":"27","author":"DeKosky","year":"2006","journal-title":"Neurobiol. Aging."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/ajmg.b.30068","article-title":"Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer\u2019s disease suggests choline acetyltransferase as a candidate deserving further study","volume":"132","author":"Cook","year":"2005","journal-title":"Amer. J. Med. Gen. Part B Neuropsychiatr. Genet."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0304-3940(03)00380-X","article-title":"Lack of association between a single nucleotide polymorphism within the choline acetyltransferase gene and patients with Alzheimer\u2019s disease","volume":"343","author":"Schwarz","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1742-2094-2-4","article-title":"Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures","volume":"2","author":"Carnevale","year":"2005","journal-title":"J. Neuroinflammation."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2174\/1574889811308020003","article-title":"New advances in pharmacological approaches to the cholinergic system: An overview on muscarinic receptor ligands and cholinesterase inhibitors","volume":"8","author":"Greig","year":"2013","journal-title":"Recent Pat. CNS Drug Discov."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bbi.2005.03.015","article-title":"The cholinergic anti-inflammatory pathway","volume":"19","author":"Pavlov","year":"2005","journal-title":"Brain Behav. Immun."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"9809","DOI":"10.3390\/ijms15069809","article-title":"Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity","volume":"15","author":"Pohanka","year":"2014","journal-title":"Int. J. Mol. Sci."}],"container-title":["Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-9721\/9\/2\/29\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:59:43Z","timestamp":1760363983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-9721\/9\/2\/29"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,12]]},"references-count":130,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["diseases9020029"],"URL":"https:\/\/doi.org\/10.3390\/diseases9020029","relation":{},"ISSN":["2079-9721"],"issn-type":[{"value":"2079-9721","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,12]]}}}