Amino Acid Metabolism in Rheumatoid Arthritis: Friend or Foe?

Abstract

In mammals, amino acid metabolism has evolved to act as a critical regulator of innate and adaptive immune responses. Rheumatoid arthritis (RA) is the most common form of inflammatory arthropathy sustained by autoimmune responses. We examine here the current knowledge of tryptophan and arginine metabolisms and the main immunoregulatory pathways in amino acid catabolism, in both RA patients and experimental models of arthritis. We found that l-tryptophan (Trp) metabolism and, in particular, the kynurenine pathway would exert protective effects in all experimental models and in some, but not all, RA patients, possibly due to single nucleotide polymorphisms in the gene coding for indoleamine 2,3-dioxygenase 1 (IDO1; the enzyme catalyzing the rate-limiting step of the kynurenine pathway). The function, i.e., either protective or pathogenetic, of the l-arginine (Arg) metabolism in RA was less clear. In fact, although immunoregulatory arginase 1 (ARG1) was highly induced at the synovial level in RA patients, its true functional role is still unknown, possibly because of few available preclinical data. Therefore, our analysis would indicate that amino acid metabolism represents a fruitful area of research for new drug targets for a more effective and safe therapy of RA and that further studies are demanding to pursue such an important objective.

The Gut Microbiome and Metabolites Are Altered and Interrelated in Patients With Rheumatoid Arthritis

“…In addition, 3-HAA suppresses the LPS-induced inflammatory response in macrophages through inhibition of the nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) pathway (Lee et al, 2016). A decrease in 3-HAA was also found in the serum of RA patients (Panfili et al, 2020). Recently, studies have continually appeared suggesting that other autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis, also have an obvious relationship with altered tryptophan metabolism (Brown et al, 2020).…”

Coupling of Co-expression Network Analysis and Machine Learning Validation Unearthed Potential Key Genes Involved in Rheumatoid Arthritis

“…Indeed, MMP9 is distinctly increased in serum, and especially in the synovial fluid of RA patients, partially through conferring synovial fibroblast with survival benefits, thereby inducing inflammation and degradation of the cartilage (Xue et al, 2014 ). Moreover, ARG1 was reported to be strongly associated with polyamine and nitric oxide (NOS) in RA, and high ARG1 activity is considered as a frequent feature for RA patients (Panfili et al, 2020 ). In contrast, pivotal genes, such as MAGED1, RAB11FIP3 , and PUS1 , that were correlated with the vast majority of the turquoise module genes were less prominent at protein level.…”

Identification of Key Biomarkers and Immune Infiltration in Systemic Juvenile Idiopathic Arthritis by Integrated Bioinformatic Analysis

“…The arginase 1 (ARG1) gene encodes arginase type I, which metabolizes L-arginine to L-ornithine and urea. In human, arginase one is constitutively expressed in polymorphonuclear neutrophils, and acts as a key regulator of innate immunity and adaptive immunity (Panfili et al, 2020). It is liberated from neutrophils in some inflammatory diseases such as glomerular acute immune complex inflammation, and it reduces the L-arginine bioavailability and downregulates the levels of NO through substrate competition, which in turn suppresses immune responses (Waddington et al, 1998;Munder, 2009;Chang et al, 2020;Sim et al, 2021).…”