Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa
Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa
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DOI：
10.1172/jci.insight.140598
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发表时间：
2020-10-15
期刊：
影响因子：
8
通讯作者：
Demangel, Caroline
中科院分区：
文献类型：
--
作者：
Guenin-Mace, Laure;Morel, Jean-David;Demangel, Caroline
化脓性汗腺炎（HS）是一种病因不明的慢性皮肤病，表现为复发性疼痛性病变。皮肤生态失调和未解决的炎症是活动性HS的标志，但它们的起源和相互作用仍不清楚。我们的HS皮肤的代谢组学分析揭示了皮肤成纤维细胞中色氨酸catenin的犬尿氨酸途径的异常诱导，与炎性细胞浸润释放犬尿氨酸途径诱导细胞因子相关。值得注意的是，病变皮肤中犬尿氨酸途径的过度活化与色氨酸的局部和全身消耗相关。然而，皮肤微生物群通常将宿主色氨酸降解为吲哚，通过芳烃受体（AHR）的接合来调节组织炎症。在HS皮肤病变中，我们检测到AHR激活的背景缺陷与细菌衍生的AHR激动剂的产生受损以及常驻植物群中产生AHR配体的细菌的发生率降低相一致。因此，皮肤-微生物群界面处的葡聚糖催化剂的失调提供了一种将HS病变的免疫学和微生物学特征联系起来的机制。除了揭示HS患者的代谢改变外，我们的研究还表明，纠正AHR信号传导将有助于恢复HS皮肤的免疫稳态。
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 tryptopha n 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.