Arginine-dependent immune responses

Abstract

A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.

Reduced L-Arginine and L-Arginine-ADMA-Ratio, and Increased SDMA after Norseman Xtreme Triathlon

“…Reduced levels of L-arginine are also known to cause both pro-inflammatory and anti-inflammatory effects through effects upon macrophages, dendritic cells, and T-cells, as reviewed by Líndez and Reith [ 36 ]. It is also known that Ironman distance triathlons causes a state with increased circulatory cytokines, muscle damage markers, and leukocytosis [ 1 , 2 , 3 , 4 ].…”

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

“…Alternatively, ARG2 is a mitochondrial enzyme that is commonly expressed in extrahepatic tissues, most prominently in the kidney. While ARG1 plays a fundamental role in inflammation-associated immunosuppression, both ARG isoforms have been linked to vascular disease by triggering EC dysfunction [ 10 , 11 , 12 , 13 , 14 , 15 ]. ARG-derived urea is readily excreted by the kidneys while ornithine is further metabolized by ornithine decarboxylase (ODC) to putrescine and the downstream polyamines, spermine, and spermidine [ 23 ].…”

“…Considerable evidence has established an important role for iNOS and ARG1 in the modulation of immune responses via the catabolism of arginine. Macrophages display distinct phenotypic heterogeneity and canonical classifications divide activated macrophages into two functional subsets: M1 or classically activated and M2 or alternatively activated [ 11 ]. However, this grouping is an oversimplification as macrophages exist in a continuum between these two functional states.…”

“…Currently, two promising ARG inhibitors are used in clinical trials: Numidargistat for cancer immunotherapy and CB-280 for cystic fibrosis treatment [ 163 ]. Curiously, many comorbidities which increase the risk of infection and poor outcomes in COVID-19, such as diabetes, hypertension, cardiovascular disease, chronic kidney disease, and old age, are associated with endothelial dysfunction and high ARG activity [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 164 ]. The elevation in ARG expression in these highly vulnerable patient groups, who are likely to respond favorably to strategies targeting ARG, may explain the adverse outcomes in these patients.…”

“…The metabolism of arginine serves as a key regulator of innate and adaptive immunity [ 7 , 8 , 9 , 10 , 11 ]. Arginine catabolism in myeloid cells is largely driven by nitric oxide (NO) synthase (NOS) and arginase (ARG), and the differential regulation of these enzymes augments or diminishes the immune response.…”