title: Functional expression of aryl hydrocarbon receptor on mast cells populating human endometriotic tissues.
abstract: Endometriosis is an inflammatory disease characterized by the presence of ectopic endometrial tissue outside the uterus. A diffuse infiltration of mast cells (MCs) is observed throughout endometriotic lesions, but little is known about how these cells contribute to the network of molecules that modulate the growth of ectopic endometrial implants and promote endometriosis-associated inflammation. The aryl hydrocarbon receptor (AhR), a transcription factor known to respond to environmental toxins and endogenous compounds, is present in MCs. In response to AhR activation, MCs produce IL-17 and reactive oxygen species, highlighting the potential impact of AhR ligands on inflammation via MCs. Here, we investigated the possibility that endometrial MCs promote an inflammatory microenvironment by sensing AhR ligands, thus sustaining endometriosis development. Using human endometriotic tissue (ET) samples, we performed the following experiments: (i) examined the cytokine expression profile; (ii) counted AhR-expressing MCs; (iii) verified the phenotype of AhR-expressing MCs to establish whether MCs have a tolerogenic (IL-10-positive) or inflammatory (IL-17-positive) phenotype; (iv) measured the presence of AhR ligands (tryptophan-derived kynurenine) and tryptophan-metabolizing enzymes (indoleamine 2,3-dioxygenase 1 (IDO1)); (v) treated ET organ cultures with an AhR antagonist in vitro to measure changes in the cytokine milieu; and (vi) measured the growth of endometrial stromal cells cultured with AhR-activated MC-conditioned medium. We found that ET tissue was conducive to cytokine production, orchestrating chronic inflammation and a population of AhR-expressing MCs that are both IL-17 and IL-10-positive. ET was rich in IDO1 and the AhR-ligand kynurenine compared with control tissue, possibly promoting MC activation through AhR. ET was susceptible to treatment with an AhR antagonist, and endometrial stromal cell growth was improved in the presence of soluble factors released by MCs on AhR activation. These results suggest a new mechanistic role of MCs in the pathogenesis of endometriosis.
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mariuzzi
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Domenis
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Orsaria
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzinotto
authors.affiliation: Clinic of Obstetrics and Gynecology, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Ambrogio P
authors.initials: AP
authors.lastname: Londero
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Bulfoni
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Candotti
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zanello
authors.affiliation: Section of Applied Physics, Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Ballico
authors.affiliation: Section of Applied Physics, Department of Medical and Biological Sciences, University of Udine, P.le Kolbe 4, 33100 Udine, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mimmi
authors.affiliation: Clinic of Obstetrics and Gynecology, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Clinic of Obstetrics and Gynecology, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Marchesoni
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Di Loreto
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Antonio P
authors.initials: AP
authors.lastname: Beltrami
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.affiliation: Section of Surgical Pathology, Department of Medical and Biological Sciences, University Hospital of Udine, P.le S.Maria della Misericordia 15, 33100 Udine, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gri
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004715:Endometriosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008024:Ligands; D008407:Mast Cells / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D016207:Cytokines; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018836:Inflammation Mediators; D020381:Interleukin-17; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D016753:Interleukin-10; D007737:Kynurenine