title: The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs.
abstract: A controlled inflammatory response is required for protection against infection, but persistent inflammation causes tissue damage. Dendritic cells (DCs) have a unique capacity to promote both inflammatory and anti-inflammatory processes. One key mechanism involved in DC-mediated immunosuppression is the expression of tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO has been implicated in diverse processes in health and disease but its role in endotoxin tolerance in human DCs is still controversial. Here we investigated the role of IDO in shaping DCs phenotype and function under endotoxin tolerance conditions. Our data show that TLR4 ligation in LPS-primed DCs, induced higher levels of both IDO isoforms together with the transcription factor aryl-hydrocarbon receptor (AhR), compared to unprimed controls. Additionally, LPS conditioning induced an anti-inflammatory phenotype in DCs - with an increase in IL-10 and higher expression of programmed death ligand (PD-L)1 and PD-L2 - which were partially dependent on IDO. Furthermore, we demonstrated that the AhR-IDO pathway was responsible for the preferential activation of non-canonical NF-κB pathway in LPS-conditioned DCs. These data provide new insight into the mechanisms of the TLR4-induced tolerogenic phenotype in human DCs, which can help the better understanding of processes involved in induction and resolution of chronic inflammation and tolerance.
authors.affiliation: Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom.
authors.forename: Fabián
authors.initials: F
authors.lastname: Salazar
authors.affiliation: Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom.
authors.forename: Dennis
authors.initials: D
authors.lastname: Awuah
authors.affiliation: Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom.|Medical Microbiology and Immunology Department, Mansoura University, Egypt.
authors.forename: Ola H
authors.initials: OH
authors.lastname: Negm
authors.affiliation: Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom.
authors.forename: Farouk
authors.initials: F
authors.lastname: Shakib
authors.affiliation: Division of Immunology, School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom.
authors.forename: Amir M
authors.initials: AM
authors.lastname: Ghaemmaghami
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D060890:B7-H1 Antigen; D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10; D015847:Interleukin-4; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D016328:NF-kappa B; D061027:Programmed Cell Death 1 Ligand 2 Protein; D017346:Protein Serine-Threonine Kinases; D018336:Receptors, Aryl Hydrocarbon; D011956:Receptors, Cell Surface; D048008:TNF Receptor-Associated Factor 3; D051197:Toll-Like Receptor 4; D051841:Transcription Factor RelB; D000097782:NF-kappaB-Inducing Kinase; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C111235:AHR protein, human; C423236:CD274 protein, human; C576710:IDO1 protein, human; C576711:IDO2 protein, human; C508609:IL10 protein, human; C508598:IL4 protein, human; C556977:PDCD1LG2 protein, human; C497593:RELB protein, human; C495345:TLR4 protein, human; C090656:TRAF3 protein, human