Kynurenine Pathway Metabolites Alone Do Not Alter Schwann Cell Metabolism: Toward an Infection-Dependent Mechanism in Leprosy Neuropathy

Leprosy is a neglected infectious disease caused by Mycobacterium leprae, a pathogen with a unique tropism for peripheral nerves, where it infects Schwann cells (SCs) and triggers inflammatory responses that can culminate in irreversible neuropathy (Expert Rev. Clin. Immunol. (2015) 11:391). Despite nerve damage being the major cause of disability in leprosy, the metabolic mechanisms underlying SC dysfunction remain poorly understood. Tryptophan catabolism through indoleamine 2,3-dioxygenase 1 (IDO1) generates kynurenine pathway metabolites with immunomodulatory and neuroactive properties, whose dysregulation has been implicated in neurodegeneration (Microbes Infect. (2017) 19:505; Clin. Exp. Immunol. (2011) 165:251; Eur. J. Immunol. (2012) 42:2925). Previous studies from our group demonstrated increased IDO1 expression and activity in leprosy lesions and patient serum, as well as IDO1 induction by M. leprae in immune cells and SCs, supporting a potential role for the kynurenine pathway in leprosy neuropathy (Cells (2025) 14:1550; Pereira (2020)). Here, we investigated whether kynurenine metabolites (quinolinic, kynurenic, picolinic, and 3-hydroxyanthranilic acids) directly affect human SC viability and metabolism. Under the experimental conditions tested, none of the metabolites significantly affected SC viability by crystal violet staining or LDH release. Metabolic responses were evaluated by extracellular glucose consumption and lactate production and likewise, the metabolism of the treated cells remained comparable to untreated controls. These findings indicate that kynurenine metabolites alone do not exert direct cytotoxic effects or markedly alter glycolytic metabolism in SCs. However, their biological effects may depend on the presence of M. leprae, as infected SCs may respond differently to these metabolites which the interaction may be critical for understanding the metabolic alterations associated with leprosy neuropathy (Microbes Infect. (2017) 19:505).