Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity

Abstract

Arginine metabolism has been a key catabolic and anabolic process throughout the evolution of the immune response. Accruing evidence indicates that arginine-catabolizing enzymes, mainly nitric oxide synthases and arginases, are closely integrated with the control of immune response under physiological and pathological conditions. Myeloid cells are major players that exploit the regulators of arginine metabolism to mediate diverse, although often opposing, immunological and functional consequences. In this article, we focus on the importance of arginine catabolism by myeloid cells in regulating innate and adaptive immunity. Revisiting this matter could result in novel therapeutic approaches by which the immunoregulatory nodes instructed by arginine metabolism can be targeted.

Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

“…The initial M1/M2 paradigm was drawn on the competing activities of Arginase (Arg) and Nitric Oxide Synthase (Nos) for Arginine. When Arg is highly expressed, no or little NO can be generated, changing the biological properties of the cells and their environment (Mills et al, 2000;Rath et al, 2014;Rodriguez et al, 2017). However, before and after the onset of dietinduced obesity eWAT macrophages lack expression of both Arg and iNOS (Nos2).…”

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…On the other hand, neighboring cells may deplete amino acids that are essential for mTORC1 activation in tissue-resident immune cells (Figure 3). One scenario in which this occurs is when activated innate immune cells expressing Arginase 1 consume arginine, and in this way assume a regulatory role by depriving T cells of arginine and thereby blunting their activation (Rodriguez et al, 2017). Mechanistically, arginine sensing in T cells has been reported to depend on the binding of arginine, transported via Slc38a9, to Castor1, thereby disrupting its inhibitory interaction with Gator2, a protein that positively regulates the RAG GTPase-mediated recruitment of mTORC1 to lysosomes (Chantranupong et al, 2016).…”

“…Mechanistically, arginine sensing in T cells has been reported to depend on the binding of arginine, transported via Slc38a9, to Castor1, thereby disrupting its inhibitory interaction with Gator2, a protein that positively regulates the RAG GTPase-mediated recruitment of mTORC1 to lysosomes (Chantranupong et al, 2016). Depriving T cells of arginine is one of the core mechanisms through which myeloid-derived suppressor cells (MDSCs) and alternatively activated macrophages limit Teff cell function (Figure 3; Murray, 2016; Rodriguez et al, 2017). …”

T‐cell cross‐reactivity may explain the large variation in how cancer patients respond to checkpoint inhibitors

“…IDO reduces the local tryptophan concentration and produces immunosuppressive metabolites such as kynurenine . Macrophages and MDSCs also produce the immunosuppressive enzyme ARG‐1, which is involved in the metabolism of the amino acid L‐arginine . Being not produced by T cells, both tryptophan and L‐arginine are critical for T‐cell proliferation.…”

“…17 Macrophages and MDSCs also produce the immunosuppressive enzyme ARG-1, which is involved in the metabolism of the amino acid L-arginine. 18 Being not produced by T cells, both tryptophan and L-arginine are critical for T-cell proliferation. Moreover, rigorous production of interleukin-10 by tumours and myeloid cells has been shown to block the maturation of dendritic cells (DCs), resulting in the accumulation of immature DCs with reduced expression of costimulatory molecules (CD80/ CD86).…”