Regulated Arginine Metabolism in Immunopathogenesis of a Wide Range of Diseases: Is There a Way to Pass between Scylla and Charybdis?

Abstract

More than a century has passed since arginine was discovered, but the metabolism of the amino acid never ceases to amaze researchers. Being a conditionally essential amino acid, arginine performs many important homeostatic functions in the body; it is involved in the regulation of the cardiovascular system and regeneration processes. In recent years, more and more facts have been accumulating that demonstrate a close relationship between arginine metabolic pathways and immune responses. This opens new opportunities for the development of original ways to treat diseases associated with suppressed or increased activity of the immune system. In this review, we analyze the literature describing the role of arginine metabolism in the immunopathogenesis of a wide range of diseases, and discuss arginine-dependent processes as a possible target for therapeutic approaches.

Keywords: COVID-19; L-arginine; autoimmunity; enzyme-based therapy; immune response; immunometabolism; immunotherapy; infectious disease; oncology.

Figure 1

L-Arginine metabolism in tumor growth immunopathogenesis and arginine-dependent processes as a target of therapeutic approaches. Expression of arginases by tumor cells promotes their proliferation and metastasis. Arginase-mediated depletion of L-Arg in the tumor microenvironment contributes to the development of immunosuppression. Tumors also induce arginase in the microenvironment. Tumor-infiltrating arginase-expressing MDSC metabolites stimulate tumor mutagenesis, reinforce immunosuppression, decrease CD3z, CD25, CD69 expressions in T cells and IL-2 production. Therapeutic strategies: Arginine-hydrolyzing enzymes result in L-Arg exhaustion in tumor microenviroment and inhibit tumor cell proliferation. Administration of ARG inhibitors decreases tumor growth/metastasis. L-Arg supplement restores T cell functions. Reengineering CAR-T cells increases ASS1 and OTC expression to improve T cell L-arg bioavailability. Elaboration ARG1-specific CD4+ and CD8+ T cell promotes arginase-positive cell elimination. ADI-PEG20, pegylated arginine deiminase; ARG1, arginase 1; ARG2, arginase 2; ASS1, argininosuccinate synthase; CAR-T, chimeric antigen receptor T cells; L-arg, L-arginine; MDSCs, myeloid derived suppressor cells; OTC, ornithine transcarbamylase; rhARG, recombinant human arginase.

Figure 2

L-Arginine metabolism in rheumatoid arthritis immunopathogenesis and arginine-dependent processes as a target of therapeutic approaches. Increased synovial fluid L-Arg in RA patients correlates with IL-1β, IL-6 and IL-8 levels. A high level of CAT-1 in sinovial fibroblasts increases L-Arg bioavailibility. A high L-Arg level promotes Th17 polarization and activation, which supports neutrophilic inflammation and cartilage destruction. Therapeutic strategies: CAT-1 knockdown with siRNA inhibite L-Arg uptake. L-Arg exhaustion with arginine-hydrolazing enzymes affects Th17 clonal expansion, iNOS activity and RNS production. ADI-PEG20, pegylated arginine deiminase; CAT-1, cationic amino acid transporter-1; IL, interleukin; L-Arg, L-arginine; Neu, neutrophil; rhARG, recombinant human arginase; siRNA, small interfering RNA; Th17, T helper 17.

Figure 3

L-Arginine metabolism in viral infection immunopathogenesis and arginine-dependent processes as a target of therapeutic approaches. Inflammatory cues such as prostaglandin E2, TNFα, IL-6, IL-1β and calgranulin B contribute to MDSC expansion. MDSCs, expressing high levels of ARG1 and iNOS, limit L-Arg availability for proliferating T cells. Decreased blood L-Arg level results in platelet activation. L-Arg supplement reduces peripheral blood level of IL-2, IL-6, and IFNγ and increases IL-10. Therapeutic strategies: L-Arg deprivation inhibits viral replication. ADI-PEG20-mediated L-Arg depletion suppresses NO production and level of inflammatory response. ADI-PEG20, pegylated arginine deiminase; ARG1, arginase 1; IFNγ—interferon γ; IL, interleukin; iNOS, inducible nitric oxide synthase; L-Arg, L-arginine; M1, M1 macrophage; MDSCs, myeloid derived suppressor cells; PGE2, prostaglandin E2; TNFα, tumor necrosis factor α.

Figure 4

L-Arginine metabolism in bacterial infection immunopathogenesis and arginine-dependent processes as a target of therapeutic approaches. Pathogenic microbes affect L-Arg metabolism to reprogram host immune responses. Reduced L-Arg level suppresses T cell response, results in substrate depletion for iNOS, thereby reducing NO production.Therapeutic strategies: Oral administration of L-Arg reduces bacterial load and enhances T cell responses, as well as iNOS activity.ADI-PEG20, pegylated arginine deiminase; ARG, bacterial arginase; iNOS, inducible nitric oxide synthase; L-Arg, L-arginine; M1, M1 macrophage.

Figure 5

L-Arginine metabolism in trauma immunopathogenesis and arginine-dependent processes as a target of therapeutic approaches. MDSC differentiation is associated with excessive accumulation of DAMPs and other inflammatory mediators. The MDSC number, building up in injuries, accounts for decline in blood L-Arg and subsequent immunosuppression. Therapeutic strategies: L-Arg supplement increases lymphoproliferative response, wound healing and lowers the risk of infectious complications. ARG, arginase; DAMPs, danger associated molecular patterns; iNOS, inducible nitric oxide synthase; L-Arg, L-arginine; MDSCs, myeloid derived suppressor cells.