title: Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis.
abstract: Amino acid catabolism has been implicated in immunoregulatory mechanisms present in several diseases, including autoimmune disorders. Our aims were to assess expression and activity of enzymes involved in Trp and Arg catabolism, as well as to investigate amino acid catabolism effects on the immune system of multiple sclerosis (MS) patients. To this end, 40 MS patients, 30 healthy control subjects, and 30 patients with other inflammatory neurological diseases were studied. Expression and activity of enzymes involved in Trp and Arg catabolism (IDO1, IDO2, Trp 2,3-dioxygenase [TDO], arginase [ARG] 1, ARG2, inducible NO synthetase) were evaluated in PBMCs. Expression of general control nonrepressed 2 serine/threonine kinase and mammalian target of rapamycin (both molecules involved in sensing amino acid levels) was assessed in response to different stimuli modulating amino acid catabolism, as were cytokine secretion levels and regulatory T cell numbers. The results demonstrate that expression and activity of IDO1 and ARG1 were significantly reduced in MS patients compared with healthy control subjects and other inflammatory neurological diseases. PBMCs from MS patients stimulated with a TLR-9 agonist showed reduced expression of general control nonrepressed 2 serine/threonine kinase and increased expression of mammalian target of rapamycin, suggesting reduced amino acid catabolism in MS patients. Functionally, this reduction resulted in a decrease in regulatory T cells, with an increase in myelin basic protein-specific T cell proliferation and secretion of proinflammatory cytokines. In contrast, induction of IDO1 using CTLA-4 or a TLR-3 ligand dampened proinflammatory responses. Overall, these results highlight the importance of amino acid catabolism in the modulation of the immunological responses in MS patients. Molecules involved in these pathways warrant further exploration as potential new therapeutic targets in MS.
authors.affiliation: Department of Neurology, Raúl Carrea Institute for Neurological Research, FLENI, 1428 Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Negrotto
authors.affiliation: Department of Neurology, Raúl Carrea Institute for Neurological Research, FLENI, 1428 Buenos Aires, Argentina jcorreale@fleni.org.ar.
authors.forename: Jorge
authors.initials: J
authors.lastname: Correale
mesh_terms: D000328:Adult; D001119:Arginase / Q000235:genetics; D001120:Arginine / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D008297:Male; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D001120:Arginine; D014366:Tryptophan Oxygenase; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases; D001119:Arginase