Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice

Josephine Brown, Georges Abboud, Longhuan Ma, Seung Chul Choi, Nathalie Kanda, Leilani Zeumer-Spataro, Jean Lee, Weidan Peng, Joy Cagmat, Tamas Faludi, Mansour Mohamadzadeh, Timothy Garrett, Laura Mandik-Nayak, Alexander Chervonsky, Andras Perl, Laurence Morel

Resultado de la investigación: Articlerevisión exhaustiva

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A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate T cell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus T cells processed tryptophan differently, suggesting a contribution of T cell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased T cell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and T cell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus T cells.

Idioma originalEnglish (US)
Número de artículo104241
EstadoPublished - may 20 2022
Publicado de forma externa

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