Immunoregulatory Interplay Between Arginine and Tryptophan Metabolism in Health and Disease.

Abstract

Over evolution, some amino-acid catabolic pathways have become critical checkpoints in immunity (1–3). The associated immunoregulatory effects rely on the depletion of specific amino acids in the microenvironment and/or generation of biologically active metabolites (4). Consumption of l-arginine (Arg) by arginase 1 (ARG1) represents a well-known immunoregulatory mechanism exploited by M2 macrophages (5) and myeloid-derived suppressor cells (MDSCs) (6–8) in tumor settings. ARG1 is also expressed by human neutrophils (9). Indoleamine 2,3-dioxygenase 1 (IDO1)—a powerful immunosuppressive enzyme catalyzing the first, rate limiting step in l-tryptophan (Trp) catabolism—depletes Trp and produces immunoregulatory molecules collectively known as kynurenines (10–13). High IDO1 expression and catalytic activity occur in dendritic cells (DCs)—professional antigen presenting cells—in response to interferon-γ (IFN-γ) (8, 10, 11). Unlike ARG1, IDO1 is also endowed with non-enzymatic signaling activity in DCs that, in the presence of transforming growth factor-β (TGF-β) in microenvironments, leads to durable immunoregulatory effects (14, 15). In conventional DCs (cDCs), a relay pathway—marked by the sequential activation of ARG1 and IDO1—promotes a potent immunoregulatory phenotype (8, 16, 17). In this setting, spermidine, i.e., a polyamine produced downstream of the ARG1-dependent pathway (18), is capable of triggering IDO1 phosphorylation and signaling, and thus may represent the critical molecular interconnection between the two enzymes (8, 16). Here, we discuss the possible protective vs. pathogenetic roles of the interplay between IDO1 and ARG1 in reprogramming immune cell functions in neoplasia and autoimmune diseases.