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Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa
Laure Guenin-Macé, … , James P. Di Santo, Caroline Demangel
Laure Guenin-Macé, … , James P. Di Santo, Caroline Demangel
Published September 24, 2020
Citation Information: JCI Insight. 2020;5(20):e140598. https://doi.org/10.1172/jci.insight.140598.
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Research Article Dermatology Inflammation

Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa

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Abstract

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

Authors

Laure Guenin-Macé, Jean-David Morel, Jean-Marc Doisne, Angèle Schiavo, Lysiane Boulet, Véronique Mayau, Pedro Goncalves, Sabine Duchatelet, Alain Hovnanian, Vincent Bondet, Darragh Duffy, Marie-Noëlle Ungeheuer, Maïa Delage, Aude Nassif, James P. Di Santo, Caroline Demangel

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Figure 3

Immune infiltrates and dermal fibroblasts jointly contribute to Quin production in HS skin.

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Immune infiltrates and dermal fibroblasts jointly contribute to Quin pro...
(A) DAPI and Quin staining of representative HC, H-HS, and L-HS dermis sections, with mean incidence of Quin+ cells, relative to total DAPI+ cells, as measured on >5 skin sections from 3 HC and 4 patients with HS. (B) CD45, Quin, and DAPI staining of a representative L-HS dermis section, with arrows pointing to Quin+CD45+ immune cells. Quantification of CD45+ cells relative to total DAPI+ cells, CD45+ cells among Quin+ cells, and Quin+ cells among CD45+ cells. (C) Zoomed view of the area depicted in A, following Quin, vimentin, and IDO1 staining, with arrows pointing to Quin+vimentin+ IDO1+ cells. (D) Relative levels of kynurenine pathway enzyme transcripts in primary fibroblasts from 5 HC and 5 patients with HS in resting conditions (left). Fold change (FC) in gene expression following a 24-hour treatment with IFN-γ (2.5 ng/mL), relative to unstimulated controls (right). Scale bar: 50 μm. Scatter dot plots with means. *P < 0.05, **P < 0.01, ***P < 0.001 by Mann-Whitney U test, with Benjamini-Hochberg correction for multiple comparisons.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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