{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T12:14:24Z","timestamp":1793621664072,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Crohn\u2019s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22\/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using\n                    <jats:italic>in vitro<\/jats:italic>\n                    culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.1034570","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T03:06:03Z","timestamp":1665630363000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["IL-22BP production is heterogeneously distributed in Crohn\u2019s disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Aur\u00e9lie","family":"Fantou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Lagrue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Laurent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Delbos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Blandin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Jarry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Beriou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Braudeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Salabert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eros","family":"Marin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Podevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Bourreille","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9gis","family":"Josien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me C.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60751-X","article-title":"Inflammatory bowel disease: clinical aspects and established and evolving therapies","volume":"369","author":"Baumgart","year":"2007","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2025-2","article-title":"Pathway paradigms revealed from the genetics of inflammatory bowel disease","volume":"578","author":"Graham","year":"2020","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1084\/jem.20192195","article-title":"The role of IL-22 in intestinal health and disease","volume":"217","author":"Keir","year":"2020","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-017-1401-7","article-title":"Clinical importance of IL-22 cascade in IBD","volume":"53","author":"Mizoguchi","year":"2018","journal-title":"J Gastroenterol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101712","article-title":"IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease","volume":"208","author":"Geremia","year":"2011","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nm1720","article-title":"Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens","volume":"14","author":"Zheng","year":"2008","journal-title":"Nat Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33194","article-title":"IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis","volume":"118","author":"Sugimoto","year":"2008","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature16460","article-title":"Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration","volume":"528","author":"Lindemans","year":"2015","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/eji.201747183","article-title":"A catch-22: Interleukin-22 and cancer","volume":"48","author":"Hernandez","year":"2018","journal-title":"Eur J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122308","article-title":"Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model","volume":"210","author":"Kirchberger","year":"2013","journal-title":"J Exp Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.12.7090","article-title":"Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor\/IL-22","volume":"166","author":"Dumoutier","year":"2001","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature11535","article-title":"IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine","volume":"491","author":"Huber","year":"2012","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700021","article-title":"Limited presence of IL-22 binding protein, a natural IL-22 inhibitor, strengthens psoriatic skin inflammation","volume":"198","author":"Martin","year":"2017","journal-title":"J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.83","article-title":"IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis","volume":"9","author":"Martin","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah5903","article-title":"A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease","volume":"354","author":"Pelczar","year":"2016","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2013.28","article-title":"Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid","volume":"7","author":"Martin","year":"2014","journal-title":"Mucosal Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160770","article-title":"IL-22BP dictates characteristics of peyer\u2019s patch follicle-associated epithelium for antigen uptake","volume":"214","author":"Jinnohara","year":"2017","journal-title":"J Exp Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700155","article-title":"The development of steady-state activation hubs between adult LTi ILC3s and primed macrophages in small intestine","volume":"199","author":"Savage","year":"2017","journal-title":"J Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1053\/j.gastro.2020.06.033","article-title":"IL22BP mediates the antitumor effects of lymphotoxin against colorectal tumors in mice and humans","volume":"159","author":"Kempski","year":"2020","journal-title":"Gastroenterology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02934","article-title":"Long interleukin-22 binding protein isoform-1 is an intracellular activator of the unfolded protein response","volume":"9","author":"G\u00f3mez-Fern\u00e1ndez","year":"2018","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112123","article-title":"Interleukin-22: immunobiology and pathology","volume":"33","author":"Dudakov","year":"2015","journal-title":"Annu Rev Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006373","article-title":"Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy","volume":"13","author":"Kr\u00e4mer","year":"2017","journal-title":"PloS Pathog"},{"key":"B23","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.clim.2014.04.012","article-title":"From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation","volume":"153","author":"Adar","year":"2014","journal-title":"Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000370","article-title":"The number and distribution of eosinophils in the adult human gastrointestinal tract: a study and comparison of racial and environmental factors","volume":"39","author":"Matsushita","year":"2015","journal-title":"Am J Surg Pathol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2350\/11-05-0130.1","article-title":"Quantity and distribution of eosinophils in the gastrointestinal tract of children","volume":"9","author":"DeBrosse","year":"2006","journal-title":"Pediatr Dev Pathol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i27.3503","article-title":"Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders","volume":"25","author":"Loktionov","year":"2019","journal-title":"World J Gastroenterol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1212640","article-title":"CD14+CD33+ myeloid cell-CCL11-eosinophil signature in ulcerative colitis","volume":"94","author":"Lampinen","year":"2013","journal-title":"J Leukoc Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-016-4047-z","article-title":"The importance of intestinal eotaxin-1 in inflammatory bowel disease: New insights and possible therapeutic implications","volume":"61","author":"Adar","year":"2016","journal-title":"Dig Dis Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.10.7390","article-title":"Intestinal Macrophage\/Epithelial cell-derived CCL11\/Eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis","volume":"181","author":"Ahrens","year":"2008","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1016\/j.cell.2019.08.008","article-title":"Single-cell analysis of crohn\u2019s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy","volume":"178","author":"Martin","year":"2019","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.cell.2019.06.029","article-title":"Intra- and inter-cellular rewiring of the human colon during ulcerative colitis","volume":"178","author":"Smillie","year":"2019","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","first-page":"ra95","DOI":"10.1126\/scisignal.aad9887","article-title":"Human IL-22 binding protein isoforms act as a rheostat for IL-22 signaling","volume":"9","author":"Lim","year":"2016","journal-title":"Sci Signal"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12027","article-title":"IL-22, not simply a Th17 cytokine","volume":"252","author":"Rutz","year":"2013","journal-title":"Immunol Rev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.11.5397","article-title":"Cutting edge: immune cells as sources and targets of the IL-10 family members","volume":"168","author":"Wolk","year":"2002","journal-title":"J Immunol"},{"key":"B35","article-title":"Cigarette smoking-mediated macrophage reprogramming: Mechanistic insights and therapeutic implications","volume":"4","author":"Yang","year":"2018","journal-title":"J Nat Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aaz4415","article-title":"M2-like, dermal macrophages are maintained via IL-4\/CCL24-mediated cooperative interaction with eosinophils in cutaneous leishmaniasis","volume":"5","author":"Lee","year":"2020","journal-title":"Sci Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.185.12.2171","article-title":"Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes","volume":"185","author":"Forssmann","year":"1997","journal-title":"J Exp Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5334.2005","article-title":"Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells","volume":"277","author":"Sallusto","year":"1997","journal-title":"Science"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms20102440","article-title":"Pharmacological targeting of the ER-resident chaperones GRP94 or cyclophilin b induces secretion of IL-22 binding protein isoform-1 (IL-22BPi1)","volume":"20","author":"G\u00f3mez-Fern\u00e1ndez","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Sig Trans Target Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2403","article-title":"Lymphotoxin regulates commensal responses to enable diet-induced obesity","volume":"13","author":"Upadhyay","year":"2012","journal-title":"Nat Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2013.12.007","article-title":"Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells","volume":"25","author":"Upadhyay","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2014.78","article-title":"Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells","volume":"8","author":"Macho-Fernandez","year":"2015","journal-title":"Mucosal Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1053\/j.gastro.2021.10.050","article-title":"Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with crohn\u2019s disease","volume":"162","author":"Sands","year":"2022","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjab075.035","article-title":"OP36 risankizumab therapy induces improvements in endoscopic endpoints in patients with moderate-to-Severe crohn\u2019s disease: Results from the phase 3 ADVANCE and MOTIVATE studies","volume":"15","author":"Bossuyt","year":"2021","journal-title":"J Crohn\u2019s Colitis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1034570\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T03:06:07Z","timestamp":1665630367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1034570\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2022.1034570"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1034570","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.07.438837","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]},"article-number":"1034570"}}