{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:13:59Z","timestamp":1792271639343,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Giovani Ricercatori program of the University of Campania Luigi Vanvitelli"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Macrophages play a crucial role in maintaining intestinal homeostasis and can exhibit either pro-inflammatory M1 or anti-inflammatory M2 phenotypes. The cannabinoid receptor type 2 (CB2) is involved in immune regulation and may represent a therapeutic target in inflammatory bowel disease (IBD). Our study investigates the phenotype of circulating macrophages and CB2 expression in children with IBD, assessing the role of CB2 stimulation in macrophage polarization, iron metabolism, and intestinal barrier function. Macrophages were isolated from 17 children with ulcerative colitis (UC), 21 with Crohn\u2019s disease (CD), and 12 healthy controls (CTR). Cells were treated with a CB2 agonist (JWH-133) and an inverse agonist (AM630). CB2 expression and macrophage polarization were assessed by Western blot. Iron metabolism was evaluated through IL-6, hepcidin levels, FPN-1 expression, and iron concentration. Inflammation was assessed by cytokine release. An in vitro \u201cimmunocompetent gut\u201d model was used to study the effects of CB2 stimulation on macrophage polarization and intestinal barrier function. CB2 expression was reduced in IBD macrophages. Compared to controls, IBD patients showed increased M1 markers and pro-inflammatory cytokines, with a reduction in M2 markers and IL-13. Altered iron metabolism was observed, with increased [Fe3+], hepcidin release, and DMT1 expression, and reduced FPN-1. CB2 stimulation restored iron metabolism, induced M2 polarization, and improved intestinal barrier function. CB2 could represent a novel therapeutic target for IBD by modulating macrophage function, iron metabolism, and mucosal barrier restoration.<\/jats:p>","DOI":"10.3390\/ijms26083720","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T03:59:06Z","timestamp":1744689546000},"page":"3720","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3378-7869","authenticated-orcid":false,"given":"Mara","family":"Creoli","sequence":"first","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Di Paola","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"},{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, Via del Casale di San Pio V, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonietta","family":"Tarallo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohail","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erasmo","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2152-747X","authenticated-orcid":false,"given":"Massimo","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Casertano","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Colucci","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Cenni","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Maddalena","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0586-1339","authenticated-orcid":false,"given":"Annamaria","family":"Staiano","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Science, Section of Pediatrics, University of Naples \u201cFederico II\u201d, Via S. Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-6571","authenticated-orcid":false,"given":"Caterina","family":"Strisciuglio","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi de Crecchio 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Schoultz, I., and Keita, \u00c5.V. (2019). 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