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In this study, we designed, synthesized and evaluated three indole-containing potential AHR ligands (FluoAHRL: AGT-4, AGT-5 and AGT-6). All synthesized compounds were shown to emit fluorescence in the near-infrared. Their AHR agonist activity was first predicted using in silico docking studies, and then confirmed using AHR luciferase reporter cell lines. FluoAHRLs were tested in vitro using mouse peritoneal macrophages and T lymphocytes to assess their immunomodulatory properties. We then focused on AGT-5, as it illustrated the predominant anti-inflammatory effects. Notably, AGT-5 demonstrated the ability to foster anti-inflammatory regulatory T cells (Treg) while suppressing pro-inflammatory T helper (Th)17 cells in vitro. AGT-5 actively induced Treg differentiation from na\u00efve CD4+ cells, and promoted Treg proliferation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) expression and interleukin-10 (IL-10) production. The increase in IL-10 correlated with an upregulation of Signal Transducer and Activator of Transcription 3 (STAT3) expression. Importantly, the Treg-inducing effect of AGT-5 was also observed in human tonsil cells in vitro. AGT-5 showed no toxicity when applied to zebrafish embryos and was therefore considered safe for animal studies. Following oral administration to C57BL\/6 mice, AGT-5 significantly upregulated Treg while downregulating pro-inflammatory Th1 cells in the mesenteric lymph nodes. Due to its fluorescent properties, AGT-5 could be visualized both in vitro (during uptake by macrophages) and ex vivo (within the lamina propria of the small intestine). These findings make AGT-5 a promising candidate for further exploration in the treatment of inflammatory and autoimmune diseases.<\/jats:p>","DOI":"10.3390\/molecules29132988","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T05:16:18Z","timestamp":1719206178000},"page":"2988","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Development of FluoAHRL: A Novel Synthetic Fluorescent Compound That Activates AHR and Potentiates Anti-Inflammatory T Regulatory Cells"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9082-9047","authenticated-orcid":false,"given":"Natalija","family":"Joni\u0107","sequence":"first","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Koprivica","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2422-7563","authenticated-orcid":false,"given":"Christos M.","family":"Chatzigiannis","sequence":"additional","affiliation":[{"name":"Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonis D.","family":"Tsiailanis","sequence":"additional","affiliation":[{"name":"Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4096-9046","authenticated-orcid":false,"given":"Stavroula G.","family":"Kyrkou","sequence":"additional","affiliation":[{"name":"Section of Organic Chemistry & Biochemistry, Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9822-2781","authenticated-orcid":false,"given":"Eleftherios Paraskevas","family":"Tzakos","sequence":"additional","affiliation":[{"name":"Department of Biology, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3233-1341","authenticated-orcid":false,"given":"Aleksandar","family":"Pavi\u0107","sequence":"additional","affiliation":[{"name":"Laboratory for Microbial Molecular Genetics and Ecology, Institute for Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9094-5248","authenticated-orcid":false,"given":"Mirjana","family":"Dimitrijevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8880-425X","authenticated-orcid":false,"given":"Andjelina","family":"Jovanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology with Maxillofacial Surgery, Clinical Hospital Center \u201cZemun\u201d, 11080 Belgrade, 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