Dual role of arginine metabolism in establishing pathogenesis
Introduction
Arginine is a semi-essential amino acid which plays an important role during innate as well as adaptive immune responses [1••]. Arginine is a common substrate for four enzymes responsible for arginine catabolism in mammals: arginase, nitric oxide synthase (NOS), arginine decarboxylase (ADC) and arginine glycine amidinotransferase (AGAT). NOS is responsible for conversion of arginine to nitric oxide (NO) and citrulline. NO is a key player in innate immunity due to its antimicrobial potential. There are three isoforms of NOS — two constitutively expressed forms, neuronal NOS (NOS1) and endothelial NOS (NOS3), and inducible NOS (iNOS; NOS2), which is capable of high-output NO production. The rate-limiting step in NO production is the availability of arginine. The availability of arginine is determined by two factors, uptake into cells by cationic amino acid transporters (CATs) and the level of arginase [2]. Extracellular arginine is also known to increase iNOS expression at translational level by reducing the levels of phosphorylated eIF2α, eukaryotic translation initiation factor which regulates translation [3].
Arginase is a metalloenzyme which hydrolyzes l-arginine to ornithine and urea. The two isoforms of arginase exhibit differential subcellular localization and tissue distribution. Arginase I, a cytosolic enzyme, is predominantly expressed in hepatocytes. However, arginase II is a mitochondrial enzyme, and is expressed in brain, kidney, small intestine, monocytes and macrophages.
Section snippets
Arginine as an energy source during infection
Effective antimicrobial action in the intracellular environment in macrophages is brought about by molecules like nitric oxide (NO) and reactive oxygen species. The metabolism of arginine contributes to production of NO. The host cell maintains a basal level of free arginine in its cytoplasm. Intracellular pathogens like Salmonella Typhimurium, Mycobacterium tuberculosis, etc. have the ability to utilize the host arginine pool. Arginine acts as a trigger for expression of various pathogenicity
Host sources of arginine
In the host, arginine is transported via the y+, B0+, and b0+ transport systems. One such transporter system is the cationic amino acid transporter (CAT; also known as solute carrier 7A) family, which includes CAT1-4. Arginine is mostly transported by CAT1-3. CAT1 shows ubiquitous expression with the exception of liver. However, CAT2 has two splice variants CAT2A and B. CAT2A is a low affinity isoform primarily in the liver, and CAT2B is a high affinity transporter known to be abundant in
Arginine as an immune modulator: a double-edged sword
Arginine metabolism is a deciding factor in innate immune response as arginine availability is rate-limiting in NO production. Besides its role in antimicrobial defense, arginine metabolism is crucial to M1 and M2 polarization effects. M1 macrophages are proinflammatory in nature, produce NO and NO-derived peroxynitrite, and can lead to a Th1 adaptive immune response. In contrast, heightened expression arginase is a hallmark of M2 differentiation, thus giving rise to an anti-inflammatory,
Alteration of arginine metabolism by pathogens
NO produced in granuloma macrophages is a key immune response to Mycobacterium infection. Earlier data suggests that BCG infection of macrophages results in induction of arginase in an IL-6-dependent and IL-10-dependent manner [28]. In accordance, M. tuberculosis infection in Arg1-deficient mice shows higher NO production, aggravated granuloma pathology and lower bacterial burden [15, 28, 29]. Arginase I expression in hypoxic granulomas restricts the l-arginine concentration and polyamine
Arginine — a therapeutic approach
Agmatine, an intermediate metabolite in arginine metabolism, can activate α-1 adrenoreceptors and imidazolguanidine receptors. It has been shown to increase glomerular filtration and tubular reabsorption. This property of agmatine is being exploited to treat disorders related to renal dysfunction. These include chronic kidney disease (CKD), acute renal failure (ARF) and pre-eclampsia. In CKD, renal NO production decreases with declining renal function leading to infections. In ARF, changes in
Conclusion
In this review article, the importance of arginine metabolism with respect to the host and pathogen has been discussed. The uptake of arginine is by cationic amino acid transporters (CATs), which are differentially expressed in different cell types. Following uptake, arginine is metabolized by the arginine deaminase pathway, wherein agmatine, an intermediate metabolite, serves as a connecting link between energy requirements and signaling. Moreover, the balance between arginase and iNOS
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the grant Life Science Research Board (LSRB0008) and DBT-IISc partnership program for advanced research in biological sciences and bioengineering to DC. Infrastructure support from ICMR (Center for Advanced Study in Molecular Medicine), DST (FIST), and UGC (special assistance) is acknowledged. MG is supported by a fellowship from IISc, India and AD is supported by a fellowship from Department of Biotechnology, India. DC received DAE SRC outstanding Investigator award
References (45)
- et al.
l-Arginine availability regulates inducible nitric oxide synthase-dependent host defense against Helicobacter pylori
Infect Immun
(2007) - et al.
The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection
Nat Immunol
(2015) - et al.
Repression of arginase-2 expression in dendritic cells by microRNA-155 is critical for promoting T cell proliferation
J Immunol
(2014) - et al.
Arginase 1 activity worsens lung-protective immunity against Streptococcus pneumoniae infection
Eur J Immunol
(2015) - et al.
Protective role of arginase in a mouse model of colitis
J Immunol
(2004) - et al.
Modulation of the arginase pathway in the context of microbial pathogenesis: a metabolic enzyme moonlighting as an immune modulator
PLoS Pathog
(2010) - et al.
Regulation of immune responses by l-arginine metabolism
Nat Rev Immunol
(2005) - et al.
Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox
Proc Natl Acad Sci U S A
(2003) - et al.
Biosynthesis and metabolism of arginine in bacteria
Microbiol Rev
(1986) - et al.
The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung
PLOS ONE
(2014)
Role of small colony variants in persistence of Pseudomonas aeruginosa infections in cystic fibrosis lungs
Infect Drug Resist
Arginase I induction during Leishmania major infection mediates the development of disease
Infect Immun
Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival
Proc Natl Acad Sci U S A
Cationic amino acid transporters and Salmonella Typhimurium ArgT collectively regulate arginine availability towards intracellular Salmonella growth
PLoS ONE
Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation
Eur J Immunol
Krebs and his trinity of cycles
Nat Rev Mol Cell Biol
Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1
Cell Host Microbe
Inducible nitric oxide synthase and control of intracellular bacterial pathogens
Microbes Infect
Th1/Th2-regulated expression of arginase isoforms in murine macrophages and dendritic cells
J Immunol
Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens
Nat Immunol
Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide
J Biol Chem
TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability
Sci Signal
Cited by (0)
- 8
Equal contribution.