{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:57:15Z","timestamp":1790787435235,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008375","name":"Universit\u00e4t Basel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008375","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Infants affected by Hirschsprung disease (HSCR), a neurodevelopmental congenital disorder, lack ganglia of the intrinsic enteric nervous system (aganglionosis) in a variable length of the colon, and are prone to developing severe Hirschsprung-associated enterocolitis (HAEC). HSCR patients typically show abnormal dense innervation of extrinsic cholinergic nerve fibers throughout the aganglionic rectosigmoid. Cholinergic signaling has been reported to reduce inflammatory response. Consequently, a sparse extrinsic cholinergic innervation in the mucosa of the rectosigmoid correlates with increased inflammatory immune cell frequencies and higher incidence of HAEC in HSCR patients. However, whether cholinergic signals influence the pro-inflammatory immune response of intestinal epithelial cells (IEC) is unknown. Here, we analyzed colonic IEC isolated from 43 HSCR patients with either a low or high mucosal cholinergic innervation density (fiber-low versus fiber-high) as well as from control tissue. Compared to fiber-high samples, IEC purified from fiber-low rectosigmoid expressed significantly higher levels of IL-8 but not TNF-\u03b1, IL-10, TGF-\u03b21, Muc-2 or tight junction proteins. IEC from fiber-low rectosigmoid showed higher IL-8 protein concentrations in cell lysates as well as prominent IL-8 immunoreactivity compared to IEC from fiber-high tissue. Using the human colonic IEC cell line SW480 we demonstrated that cholinergic signals suppress lipopolysaccharide-induced IL-8 secretion <jats:italic>via<\/jats:italic> the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In conclusion, we showed for the first time that the presence of a dense mucosal cholinergic innervation is associated with decreased secretion of IEC-derived pro-inflammatory IL-8 in the rectosigmoid of HSCR patients likely dependent on a7nAChR activation. Owing to the association between IL-8 and enterocolitis-prone, fiber-low HSCR patients, targeted therapies against IL-8 might be a promising immunotherapy candidate for HAEC treatment.<\/jats:p>","DOI":"10.3389\/fimmu.2021.781147","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T15:44:53Z","timestamp":1652456693000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Cholinergic Signaling Attenuates Pro-Inflammatory Interleukin-8 Response in Colonic Epithelial Cells"],"prefix":"10.3389","volume":"12","author":[{"given":"Isabelle","family":"M\u00fcller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urs","family":"Kym","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Galati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha","family":"Tharakan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Subotic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Krebs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleuthere","family":"Stathopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Schmittenbecher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Cholewa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Reingruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"NIGStudy Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Holland-Cunz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Keck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.5114\/pg.2014.46160","article-title":"Diagnosis of Hirschsprung's Disease With Particular Emphasis on Histopathology","volume":"9","author":"Szylberg","year":"2014","journal-title":"A Syst Rev Curr Literature Prz Gastroenterol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.201400473","article-title":"Mucus Barriers to Microparticles and Microbes are Altered in Hirschsprung's Disease","volume":"15","author":"Yildiz","year":"2015","journal-title":"Macromol Biosci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/nrgastro.2012.234","article-title":"Development and Developmental Disorders of the Enteric Nervous System","volume":"10","author":"Obermayr","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1101\/2020.06.15.151621","article-title":"Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease","volume":"12","author":"Keck","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00292-007-0901-2","article-title":"Enzyme Histochemistry of Classical and Ultrashort Hirschsprung\u2019s Disease","volume":"28","author":"Bruder","year":"2007","journal-title":"Pathologe"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2012.07.007","article-title":"Hirschsprung-Associated Enterocolitis: Prevention and Therapy","volume":"21","author":"Frykman","year":"2012","journal-title":"Semin Pediatr Surg"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2008.10.052","article-title":"Development of a Standardized Definition for Hirschsprung's-Associated Enterocolitis: A Delphi Analysis","volume":"44","author":"Pastor","year":"2009","journal-title":"J Pediatr Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201801913R","article-title":"B-Lymphocyte-Intrinsic and -Extrinsic Defects in Secretory Immunoglobulin A Production in the Neural Crest-Conditional Deletion of Endothelin Receptor B Model of Hirschsprung-Associated Enterocolitis","volume":"33","author":"Medrano","year":"2019","journal-title":"FASEB J"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0128822","DOI":"10.1371\/journal.pone.0128822","article-title":"Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease","volume":"10","author":"Gosain","year":"2015","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201444737","article-title":"Enterocolitis Causes Profound Lymphoid Depletion in Endothelin Receptor B- and Endothelin 3-Null Mouse Models of Hirschsprung-Associated Enterocolitis","volume":"45","author":"Frykman","year":"2015","journal-title":"Eur J Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e0124172","DOI":"10.1371\/journal.pone.0124172","article-title":"Characterization of Bacterial and Fungal Microbiome in Children With Hirschsprung Disease With and Without a History of Enterocolitis: A Multicenter Study","volume":"10","author":"Frykman","year":"2015","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e0162079","DOI":"10.1371\/journal.pone.0162079","article-title":"Characterization of Intestinal Microbiomes of Hirschsprung's Disease Patients With or Without Enterocolitis Using Illumina-MiSeq High-Throughput Sequencing","volume":"11","author":"Li","year":"2016","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/s41598-018-36967-z","article-title":"Gut Microbiota-Mediated Gene-Environment Interaction in the TashT Mouse Model of Hirschsprung Disease","volume":"9","author":"Toure","year":"2019","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00326","article-title":"A Metagenomics Study on Hirschsprung's Disease Associated Enterocolitis: Biodiversity and Gut Microbial Homeostasis Depend on Resection Length and Patient's Clinical History","volume":"7","author":"Pini Prato","year":"2019","journal-title":"Front Pediatr"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1053\/j.sempedsurg.2012.07.006","article-title":"The Pathogenesis of Hirschsprung's Disease-Associated Enterocolitis","volume":"21","author":"Austin","year":"2012","journal-title":"Semin Pediatr Surg"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e99944","DOI":"10.1371\/journal.pone.0099944","article-title":"Altered Goblet Cell Differentiation and Surface Mucus Properties in Hirschsprung Disease","volume":"9","author":"Thiagarajah","year":"2014","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","first-page":"21725","DOI":"10.1038\/s41598-020-78340-z","article-title":"Analysis of Enteric Nervous System and Intestinal Epithelial Barrier to Predict Complications in Hirschsprung's Disease","volume":"10","author":"Dariel","year":"2020","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(53)80003-X","article-title":"Congenital Megacolon; a Comparison of the Spastic and Hypertrophied Segments With Respect to Cholinesterase Activities and Sensitivities to Acetylcholine, DFP and the Barium Ion","volume":"24","author":"Kamijo","year":"1953","journal-title":"Gastroenterology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-8165(72)80058-1","article-title":"The Pathophysiology of Aganglionosis of the Entire Colon (Zuelzer-Wilson Syndrome). Morphometric Investigations of the Extent of Sacral Parasympathetic Innervation of the Circular Muscles of the Aganglionic Colon","volume":"147","author":"Meier-Ruge","year":"1972","journal-title":"Beitr Pathol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(74)80114-9","article-title":"Functional Importance of Extrinsic Parasympathetic Innervation to the Distal Colon and Rectum in Man","volume":"66","author":"Devroede","year":"1974","journal-title":"Gastroenterology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3468(72)90394-6","article-title":"Acetylcholinesterase Activity in Suction Biopsies of the Rectum in the Diagnosis of Hirschsprung's Disease","volume":"7","author":"Meier-Ruge","year":"1972","journal-title":"J Pediatr Surg"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2012.05.006","article-title":"Critical Roles of Acetylcholine and the Muscarinic and Nicotinic Acetylcholine Receptors in the Regulation of Immune Function","volume":"91","author":"Kawashima","year":"2012","journal-title":"Life Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706889","article-title":"Cholinergic Regulation of Epithelial Ion Transport in the Mammalian Intestine","volume":"149","author":"Hirota","year":"2006","journal-title":"Br J Pharmacol"},{"key":"B24","doi-asserted-by":"publisher","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":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature01321","article-title":"The Inflammatory Reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2016.00062","article-title":"Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of the Alpha-7 Nicotinic Receptor","volume":"22","author":"Di Giovangiulio","year":"2016","journal-title":"Mol Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-304676","article-title":"A Distinct Vagal Anti-Inflammatory Pathway Modulates Intestinal Muscularis Resident Macrophages Independent of the Spleen","volume":"63","author":"Matteoli","year":"2014","journal-title":"Gut"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12792","article-title":"Chronic Vagus Nerve Stimulation in Crohn's Disease: A 6-Month Follow-Up Pilot Study","volume":"28","author":"Bonaz","year":"2016","journal-title":"Neurogastroenterol Motil"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00418","article-title":"Anti-Inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation","volume":"13","author":"Payne","year":"2019","journal-title":"Front Neurosci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nri2316","article-title":"Epithelial-Cell Recognition of Commensal Bacteria and Maintenance of Immune Homeostasis in the Gut","volume":"8","author":"Artis","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2004.061168","article-title":"Acute Induction of Human IL-8 Production by Intestinal Epithelium Triggers Neutrophil Infiltration Without Mucosal Injury","volume":"54","author":"Kucharzik","year":"2005","journal-title":"Gut"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1038\/s41467-021-21533-5","article-title":"The Neutrophil Antimicrobial Peptide Cathelicidin Promotes Th17 Differentiation","volume":"12","author":"Minns","year":"2021","journal-title":"Nat Commun"},{"key":"B33","first-page":"997","article-title":"Expression of Interleukin-8 Gene in Inflammatory Bowel Disease is Related to the Histological Grade of Active Inflammation","volume":"144","author":"Mazzucchelli","year":"1994","journal-title":"Am J Pathol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1136\/gut.38.2.216","article-title":"Increased Interleukin 8 Expression in the Colon Mucosa of Patients With Inflammatory Bowel Disease","volume":"38","author":"Daig","year":"1996","journal-title":"Gut"},{"key":"B35","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1097\/00054725-199503000-00005","article-title":"Increased Expression of Interleukin-8 mRNA in Ulcerative Colitis and Crohn's Disease Mucosa and Epithelial Cells","volume":"1","author":"Izutani","year":"1995","journal-title":"Inflammation Bowel Dis"},{"key":"B36","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1159\/000509110","article-title":"Predisposition of Inflammatory Bowel Disease Is Influenced by IL-8, IL-10, and IL-18 Polymorphisms: A Meta-Analysis","volume":"181","author":"Su","year":"2020","journal-title":"Int Arch Allergy Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2021.05.012","article-title":"Nerves Make the Bowel Happy, Even When the Enteric Nervous System Is Missing","volume":"12","author":"Heuckeroth","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.185","article-title":"Acetylcholine Beyond Neurons: The non-Neuronal Cholinergic System in Humans","volume":"154","author":"Wessler","year":"2008","journal-title":"Br J Pharmacol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"46","DOI":"10.7150\/ijbs.16404","article-title":"The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism","volume":"13","author":"Ren","year":"2017","journal-title":"Int J Biol Sci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1172\/JCI8066","article-title":"Salmonella Typhimurium Induces Epithelial IL-8 Expression via Ca(2+)-Mediated Activation of the NF-kappaB Pathway","volume":"105","author":"Gewirtz","year":"2000","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2172-8-1","article-title":"Transcriptional Profiling of the LPS Induced NF-kappaB Response in Macrophages","volume":"8","author":"Sharif","year":"2007","journal-title":"BMC Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41420-021-00431-1","article-title":"Vagus Nerve Stimulation Enhances the Cholinergic Anti-Inflammatory Pathway to Reduce Lung Injury in Acute Respiratory Distress Syndrome via STAT3","volume":"7","author":"Li","year":"2021","journal-title":"Cell Death Discovery"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/ni1229","article-title":"Stimulation of the Vagus Nerve Attenuates Macrophage Activation by Activating the Jak2-STAT3 Signaling Pathway","volume":"6","author":"de Jonge","year":"2005","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.06.096","article-title":"GTS-21 Inhibits Pro-Inflammatory Cytokine Release Independent of the Toll-Like Receptor Stimulated via a Transcriptional Mechanism Involving JAK2 Activation","volume":"78","author":"Kox","year":"2009","journal-title":"Biochem Pharmacol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2017.4080","article-title":"Nicotine Induces TIPE2 Upregulation and Stat3 Phosphorylation Contributes to Cholinergic Anti-Inflammatory Effect","volume":"51","author":"Sui","year":"2017","journal-title":"Int J Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit669","article-title":"Stimulation of the Alpha7 Nicotinic Acetylcholine Receptor Protects Against Sepsis by Inhibiting Toll-Like Receptor via Phosphoinositide 3-Kinase Activation","volume":"209","author":"Kim","year":"2014","journal-title":"J Infect Dis"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0061-x","article-title":"The Proximal Tubular Alpha7 Nicotinic Acetylcholine Receptor Attenuates Ischemic Acute Kidney Injury Through Akt\/PKC Signaling-Mediated HO-1 Induction","volume":"50","author":"Kim","year":"2018","journal-title":"Exp Mol Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02546","article-title":"Nicotinic Mitigation of Neuroinflammation and Oxidative Stress After Chronic Sleep Deprivation","volume":"10","author":"Xue","year":"2019","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)91064-O","article-title":"Differential Cytokine Expression by Human Intestinal Epithelial Cell Lines: Regulated Expression of Interleukin 8","volume":"105","author":"Eckmann","year":"1993","journal-title":"Gastroenterology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/j.1365-2982.2008.01252.x","article-title":"The Vagus Nerve as a Modulator of Intestinal Inflammation","volume":"21","author":"Van Der Zanden","year":"2009","journal-title":"Neurogastroenterol Motil"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3468(89)80566-4","article-title":"The Pathophysiology of Hirschsprung's-Associated Enterocolitis: Importance of Histologic Correlates","volume":"24","author":"Teitelbaum","year":"1989","journal-title":"J Pediatr Surg"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3468(97)90683-7","article-title":"Children With Hirschsprung's Disease Have an Abnormal Colonic Mucus Defensive Barrier Independent of the Bowel Innervation Status","volume":"32","author":"Aslam","year":"1997","journal-title":"J Pediatr Surg"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3468(98)90372-4","article-title":"Turnover of Radioactive Mucin Precursors in the Colon of Patients With Hirschsprung's Disease Correlates With the Development of Enterocolitis","volume":"33","author":"Aslam","year":"1998","journal-title":"J Pediatr Surg"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3468(95)90334-8","article-title":"Enterocolitis Associated With Hirschsprung's Disease: A Clinical Histopathological Correlative Study","volume":"30","author":"Elhalaby","year":"1995","journal-title":"J Pediatr Surg"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1053\/jpsu.2003.50071","article-title":"MUC-2 Mucin Production in Hirschsprung's Disease: Possible Association With Enterocolitis Development","volume":"38","author":"Mattar","year":"2003","journal-title":"J Pediatr Surg"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpedsurg.2020.06.018","article-title":"A Piglet Model of Iatrogenic Rectosigmoid Hypoganglionosis Reveals the Impact of the Enteric Nervous System on Gut Barrier Function and Microbiota Postnatal Development","volume":"56","author":"Arnaud","year":"2021","journal-title":"J Pediatr Surg"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0051-4","article-title":"Neuroimmunophysiology of the Gut: Advances and Emerging Concepts Focusing on the Epithelium","volume":"15","author":"Sharkey","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e0187773","DOI":"10.1371\/journal.pone.0187773","article-title":"Lung Epithelial Response to Cigarette Smoke and Modulation by the Nicotinic Alpha 7 Receptor","volume":"12","author":"Gahring","year":"2017","journal-title":"PLoS One"},{"key":"B59","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/1479-5876-9-129","article-title":"Anti-Inflammatory Effects of Nicotine in Obesity and Ulcerative Colitis","volume":"9","author":"Lakhan","year":"2011","journal-title":"J Transl Med"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12469","article-title":"Cholinergic Receptor Activation on Epithelia Protects Against Cytokine-Induced Barrier Dysfunction","volume":"213","author":"Dhawan","year":"2015","journal-title":"Acta Physiol (Oxf)"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.12.007","article-title":"Activation of Focal Adhesion Kinase via M1 Muscarinic Acetylcholine Receptor is Required in Restitution of Intestinal Barrier Function After Epithelial Injury","volume":"1842","author":"Khan","year":"2014","journal-title":"Biochim Biophys Acta"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1159\/000345437","article-title":"Cholinergic Modulation of Epithelial Integrity in the Proximal Colon of Pigs","volume":"197","author":"Lesko","year":"2013","journal-title":"Cells Tissues Organs"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1159\/000329982","article-title":"Nicotine Reduces TNF-Alpha Expression Through a Alpha7 Nachr\/MyD88\/NF-kB Pathway in HBE16 Airway Epithelial Cells","volume":"27","author":"Li","year":"2011","journal-title":"Cell Physiol Biochem"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e108397","DOI":"10.1371\/journal.pone.0108397","article-title":"A New IRAK-M-Mediated Mechanism Implicated in the Anti-Inflammatory Effect of Nicotine via Alpha7 Nicotinic Receptors in Human Macrophages","volume":"9","author":"Maldifassi","year":"2014","journal-title":"PLoS One"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901423","article-title":"Activation of Murine Macrophages via TLR2 and TLR4 is Negatively Regulated by a Lyn\/PI3K Module and Promoted by SHIP1","volume":"184","author":"Keck","year":"2010","journal-title":"J Immunol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aer202","article-title":"Alpha7 Nicotinic Acetylcholine Receptor Agonist GTS-21 Attenuates Ventilator-Induced Tumour Necrosis Factor-Alpha Production and Lung Injury","volume":"107","author":"Kox","year":"2011","journal-title":"Br J Anaesth"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-268037","article-title":"CHRFAM7A: A Human-Specific Alpha7-Nicotinic Acetylcholine Receptor Gene Shows Differential Responsiveness of Human Intestinal Epithelial Cells to LPS","volume":"29","author":"Dang","year":"2015","journal-title":"FASEB J"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1042\/cs0820273","article-title":"Enhanced Synthesis of Neutrophil-Activating Peptide-1\/Interleukin-8 in Active Ulcerative Colitis","volume":"82","author":"Mahida","year":"1992","journal-title":"Clin Sci (Lond)"},{"key":"B69","doi-asserted-by":"publisher","first-page":"296","DOI":"10.3109\/00365529309090244","article-title":"Neutrophil-Activating Peptide (Interleukin-8) in Colonic Mucosa From Patients With Crohn's Disease","volume":"28","author":"Izzo","year":"1993","journal-title":"Scand J Gastroenterol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2012.1692","article-title":"The lL-8 and IL-13 Gene Polymorphisms in Inflammatory Bowel Disease and Colorectal Cancer","volume":"31","author":"Walczak","year":"2012","journal-title":"DNA Cell Biol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.602395","article-title":"Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients","volume":"11","author":"Li","year":"2020","journal-title":"Front Immunol"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1696075","article-title":"Significance of the IL-8 Pathway for Immunotherapy","volume":"16","author":"Gonzalez-Aparicio","year":"2020","journal-title":"Hum Vaccin Immunother"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59150","article-title":"CX3CR1 Regulates Intestinal Macrophage Homeostasis, Bacterial Translocation, and Colitogenic Th17 Responses in Mice","volume":"121","author":"Medina-Contreras","year":"2011","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.781147\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T15:44:56Z","timestamp":1652456696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.781147\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":73,"alternative-id":["10.3389\/fimmu.2021.781147"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.781147","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,6]]},"article-number":"781147"}}