A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells

Abstract

SummaryArginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+ myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings.

Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

“…Increases in RBC levels of pyruvate and lactate as well as acyl-conjugated fatty acids may relate to diabetes and obesity, which are recurring comorbidities in the T21 population, 13 complementing previous lipidomics reports on n-6 fatty acid dysregulation in RBCs from children with T21. 18 RBC metabolic markers of T21 included purine catabolites like hypoxanthine as well as immunomodulatory/inflammationrelated metabolites like (1) conjugated bile acids (markers of alteration to the microbiome), 25 (2) the carboxylic acids fumarate and succinate, 7,26 and (3) the tryptophan oxidation product kynurenine, 27 linking the present observations with the autoimmune and inflammatory comorbidities of DS. 13,14 Increases in plasma purines, specifically adenosine and its deaminated byproducts, have been previously reported in individuals with DS, where increased adenosine deaminase activity and hyperuricemia result from excessive purine synthesis secondary to the overexpression of genes in the purine de novo synthesis pathway GARS-AIRS-GART located on chromosome 21.…”

Ancillary Activity: Beyond Core Metabolism in Immune Cells

“…In line with a generally suppressive role for polyamines in the myeloid lineage, recent work from Grohman and colleagues reports an important function for spermidine in conferring immunomodulatory properties to dendritic cells (DCs) (Mondanelli et al, 2017). Specific subsets of immune cells express indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme that degrades tryptophan, an amino acid essential for effective T cell responses.…”

Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive ‘Cold’ Tumors ‘Hot’

“…This connection is not only involved in T cell anergy but also in the generation of myeloid-derived suppressor cells (MDSC), as indicated by earlier studies [46, 47]. Further, recent work clearly connects IDO1, arginase and polyamines in MDSC accumulation and function [48, 49]. In summary, IDO1 is the focus of numerous major pro-inflammatory pathways in cancer where it acts as a pivotal modifier of disease progression.…”