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.

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…Our study does not support the reduced expression of IDO1 and ARG1 in PBMCs from Argentinian patients with clinically definite, relapsing–remitting MS 14. To explain differences in study outcomes, 62% of the Argentinian cohort were taking IFN‐β1α or glatiramer acetate.…”

“…It remains possible that single or multiple cell subsets express increased levels of the enzymes. Both decreases 14 and increases 20 in ARG1 in monocytes from MS patients have been previously reported.…”

“…These subsets were chosen because they can represent more than 10% of circulating PBMCs in the groups under analysis and have been shown previously to express significant levels of IDO and ARG 14. No significant associations were observed with any cell population in the three blood donor groups suggesting the increase in IDO and ARG expression observed in CIS and MS was not linked to elevated numbers of a specific cell subset (data not shown).…”

“…A recent study from Argentina of patients with relapsing–remitting MS (mean duration of disease of 5.2 years) suggested that circulating blood cells of MS patients expressed reduced levels of IDO1 and ARG1 14. This would provide a proinflammatory environment with increased availability of Trp and Arg for the Th1‐ and Th17‐driven autoimmune responses associated with MS pathogenesis 15.…”

“…2 In human peripheral blood cells from healthy individuals, approximately 70% of mRNA for IDO1 and ARG1 are expressed by CD14 + cells, 15% by CD4 + T cells, 10% by CD8 + T cells and 5% by B cells. 14 A recent study from Argentina of patients with relapsing-remitting MS (mean duration of disease of 5.2 years) suggested that circulating blood cells of MS patients expressed reduced levels of IDO1 and ARG1. 14 This would provide a proinflammatory environment with increased availability of Trp and Arg for the Th1-and Th17-driven autoimmune responses associated with MS pathogenesis.…”