The aryl hydrocarbon receptor modulates acute and late mast cell responses.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.
Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
Riccardo
R
Sibilano
Barbara
B
Frossi
Marco
M
Calvaruso
Luca
L
Danelli
Elena
E
Betto
Alessandra
A
Dall'Agnese
Claudio
C
Tripodo
Mario P
MP
Colombo
Carlo E
CE
Pucillo
Giorgia
G
Gri
D000707:Anaphylaxis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008024:Ligands; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D017455:Receptors, IgE / Q000502:physiology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D020381:Interleukin-17; D015850:Interleukin-6; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D017455:Receptors, IgE