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

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.

The Mechanisms of L-Arginine Metabolism Disorder in Endothelial Cells.

L-arginine is a key metabolite for nitric oxide production by endothelial cells, as well as signaling molecule of the mTOR signaling pathway. mTOR supports endothelial cells homeostasis and regulates activity of L-arginine-metabolizing enzymes, endothelial nitric oxide synthase, and arginase II. Disruption of the L-arginine metabolism in endothelial cells leads to the development of endothelial dysfunction. Conflicting results of the use of L-arginine supplement to improve endothelial function reveals a controversial role of the amino acid in the endothelial cell biology. The review is aimed at analysis of the current data on the role of L-arginine metabolism in the development of endothelial dysfunction.

Sarcoidosis-related autoimmune inflammation in COVID-19 convalescent patients.

Currently, there are a large number of reports about the development of autoimmune conditions after COVID-19. Also, there have been cases of sarcoid-like granulomas in convalescents as a part of the post-COVID-19 syndrome. Since one of the etiological theories of sarcoidosis considers it to be an autoimmune disease, we decided to study changes in the adaptive humoral immune response in sarcoidosis and SARS-CoV-2 infection and to find out whether COVID-19 can provoke the development of sarcoidosis. This review discusses histological changes in lymphoid organs in sarcoidosis and COVID-19, changes in B cell subpopulations, T-follicular helper cells (Tfh), and T-follicular regulatory cells (Tfr), and analyzes various autoantibodies detected in these pathologies. Based on the data studied, we concluded that SARS-CoV-2 infection may cause the development of autoimmune pathologies, in particular contributing to the onset of sarcoidosis in convalescents.

Streptococcal arginine deiminase regulates endothelial inflammation, mTOR pathway and autophagy.

Endothelial cells (EC) are active participants in the inflammation process. During the infection, the change in endothelium properties provides the leukocyte infiltrate formation and restrains pathogen dissemination due to coagulation control. Pathogenic microbes are able to change the endothelium properties and functions in order to invade the bloodstream and disseminate in the host organism. Arginine deiminase (ADI), a bacterial arginine-hydrolyzing enzyme, which causes the amino acid deficiency, important for endothelium biology. Previous research implicates altered metabolism of arginine in the development of endothelial dysfunction and inflammation. It was shown that arginine deficiency, as well as overabundance affects the balance of mechanical target of rapamycin (mTOR)/S6 kinase (S6K) pathway, arginase and endothelial nitric oxide synthase (eNOS) resulted in reactive oxygen species (ROS) production and EC activation. ADI creating a deficiency of arginine can interfere cellular arginine-dependent processes. Thus, this study was aimed at investigation of the influence of streptococcal ADI on the metabolism and inflammations of human umbilical vein endothelial cells (HUVEC). The action of ADI was studied by comparing the effect Streptococcus pyogenes M49-16 paternal strain expressing ADI and its isogenic mutant M49-16delArcA with the inactivated gene ArcA. Based on comparison of the parental and mutant strain effects, it can be concluded, that ADI suppressed mTOR signaling pathway and enhanced autophagy. The processes failed to return to the basic level with arginine supplement. Our study also demonstrates that ADI suppressed endothelial proliferation, disrupted actin cytoskeleton structure, increased phospho-NF-κB p65, CD62P, CD106, CD54, CD142 inflammatory molecules expression, IL-6 production and lymphocytes-endothelial adhesion. In spite of the ADI-mediated decrease in arginine concentration in the cell-conditioned medium, the enzyme enhanced the production of nitric oxide in endothelial cells. Arginine supplementation rescued proliferation, actin cytoskeleton structure, brought NO production to baseline and prevented EC activation. Additional evidence for the important role of arginine bioavailability in the EC biology was obtained. The results allow us to consider bacterial ADI as a pathogenicity factor that can potentially affect the functions of endothelium.

Streptococcal Arginine Deiminase Inhibits T Lymphocyte Differentiation In Vitro.

Pathogenic microbes use arginine-metabolizing enzymes as an immune evasion strategy. In this study, the impact of streptococcal arginine deiminase (ADI) on the human peripheral blood T lymphocytes function in vitro was studied. The comparison of the effects of parental strain (Streptococcus pyogenes M49-16) with wild type of ArcA gene and its isogenic mutant with inactivated ArcA gene (Streptococcus pyogenes M49-16delArcA) was carried out. It was found that ADI in parental strain SDSC composition resulted in a fivefold decrease in the arginine concentration in human peripheral blood mononuclear cell (PBMC) supernatants. Only parental strain SDSCs suppressed anti-CD2/CD3/CD28-bead-stimulated mitochondrial dehydrogenase activity and caused a twofold decrease in IL-2 production in PBMC. Flow cytometry analysis revealed that ADI decreased the percentage of CM (central memory) and increased the proportion of TEMRA (terminally differentiated effector memory) of CD4+ and CD8+ T cells subsets. Enzyme activity inhibited the proliferation of all CD8+ T cell subsets as well as CM, EM (effector memory), and TEMRA CD4+ T cells. One of the prominent ADI effects was the inhibition of autophagy processes in CD8+ CM and EM as well as CD4+ CM, EM, and TEMRA T cell subsets. The data obtained confirm arginine's crucial role in controlling immune reactions and suggest that streptococcal ADI may downregulate adaptive immunity and immunological memory.

Protective Role of Mytilus edulis Hydrolysate in Lipopolysaccharide-Galactosamine Acute Liver Injury.

Acute liver injury in its terminal phase trigger systemic inflammatory response syndrome with multiple organ failure. An uncontrolled inflammatory reaction is difficult to treat and contributes to high mortality. Therefore, to solve this problem a search for new therapeutic approaches remains urgent. This study aimed to explore the protective effects of M. edulis hydrolysate (N2-01) against Lipopolysaccharide-D-Galactosamine (LPS/D-GalN)-induced murine acute liver injure and the underlying mechanisms. N2-01 analysis, using Liquid Chromatography Mass Spectrometry (LCMS) metabolomic and proteomic platforms, confirmed composition, molecular-weight distribution, and high reproducibility between M. edulis hydrolysate manufactured batches. N2-01 efficiently protected mice against LPS/D-GalN-induced acute liver injury. The most prominent result (100% survival rate) was obtained by the constant subcutaneous administration of small doses of the drug. N2-01 decreased Vascular Cell Adhesion Molecule-1 (VCAM-1) expression from 4.648 ± 0.445 to 1.503 ± 0.091 Mean Fluorescence Intensity (MFI) and Interleukin-6 (IL-6) production in activated Human Umbilical Vein Endothelial Cells (HUVECs) from 7.473 ± 0.666 to 2.980 ± 0.130 ng/ml in vitro. The drug increased Nitric Oxide (NO) production by HUVECs from 27.203 ± 2.890 to 69.200 ± 4.716 MFI but significantly decreased inducible Nitric Oxide Synthase (iNOS) expression from 24.030 ± 2.776 to 15.300 ± 1.290 MFI and NO production by murine peritoneal lavage cells from 6.777 ± 0.373 µm to 2.175 ± 0.279 µm. The capability of the preparation to enhance the endothelium barrier function and to reduce vascular permeability was confirmed in Electrical Cell-substrate Impedance Sensor (ECIS) test in vitro and Miles assay in vivo. These results suggest N2-01 as a promising agent for treating a wide range of conditions associated with uncontrolled inflammation and endothelial dysfunction.