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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 5

Activation of AHR is defective in HS skin lesions.

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Activation of AHR is defective in HS skin lesions.
(A) The AHR pathway. ...
(A) The AHR pathway. Upon ligand binding, AHR translocates into the nucleus where association with ARNT and interaction with specific genomic sequences induce the transcription of target genes (asterisk indicates active in supraphysiological concentrations). (B) Relative levels of AHR and AHR-controlled transcripts in skin samples from HC and patients with HS. *P < 0.05, **P < 0.01 by Mann-Whitney U test for comparisons with HC, and Wilcoxon matched-pairs test for comparisons of L-HS with matched H-HS. (C) Relative expression of AHR-controlled transcripts in fibroblasts from HC and patients with HS in resting (left) or FICZ-stimulated (right) conditions. Data are from 2 independent experiments, with fibroblasts from 5 HC and 5 patients with HS. (D) Relative levels of indole metabolites in skin samples from HC and patients with HS. *P < 0.05, **P < 0.01, by Welch’s 2-sample t test for comparisons with HC and matched pairs t test for comparisons of L-HS with matched H-HS, with Benjamini-Hochberg correction for multiple comparisons.

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