Arginase: an emerging key player in the mammalian immune system

Abstract

The enzyme arginase metabolizes L-arginine to L-ornithine and urea. Besides its fundamental role in the hepatic urea cycle, arginase is also expressed the immune system of mice and man. While significant interspecies differences exist regarding expression, subcellular localization and regulation of immune cell arginase, associated pathways of immunopathology are comparable between species. Arginase is induced in murine myeloid cells mainly by Th2 cytokines and inflammatory agents and participates in a variety of inflammatory diseases by down-regulation of nitric oxide synthesis, induction of fibrosis and tissue regeneration. In humans, arginase I is constitutively expressed in polymorphonuclear neutrophils and is liberated during inflammation. Myeloid cell arginase-mediated L-arginine depletion profoundly suppresses T cell immune responses and this has emerged as a fundamental mechanism of inflammation-associated immunosuppression. Pharmacological interference with L-arginine metabolism is a novel promising strategy in the treatment of cancer, autoimmunity or unwanted immune deviation.

Figure 2

Reciprocal regulation of arginase and inducible nitric oxide synthase (iNOS) in murine myeloid cells. Downstream metabolic products of arginase and their association with components of inflammatory responses. OAT, ornithine aminotransferase; ODC, ornithine decarboxylase.

Figure 1

Arginase as part of the hepatic urea cycle. ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; CPS, carbamoyl phosphate synthetase; OTC, ornithine transcarbamoylase.

Figure 3

Opposing roles of L-arginine in tumour biology. L-arginine can directly support tumour growth and myeloidcell arginase-mediated or pharmacological depletion (PEG-ADI/rhArg-PEG) of the amino acid inhibits tumour growth. L-arginine deficiency, in contrast, can also suppress anti-tumour immune responses by down-regulating key functions of T lymphocytes. Pharmacological interference with arginase-mediated L-arginine depletion is demonstrated here in the context of myeloid-derived suppressor cell (MDSC)-associated immune suppression. T cell functions are restored by direct inhibition of cell-bound or liberated arginase I by arginase inhibitors, by supplementation of L-arginine or L-citrulline (for regeneration of L-arginine via the L-citrulline-L-arginine cycle) and by inhibition of various arginase-inducing mechanisms in MDSC. ARG I, arginase I; COX 2, cyclooxygenase 2; PDE5, phosphodiesterase 5; PEG-ADI, pegylated arginine deiminase; rhArg-PEG, recombinant human pegylated arginase; T, T lymphocyte.