Table 1.

Arginase-dependent pathological conditions, proposed trigger signals, and mechanisms.

Pathology	Animal/Cell Line Model	Arginase Levels	Proposed Trigger Signal	Proposed Disease Mechanism	Ref.
Diabetes-induced vasculo-pathy	Bovine aortic endothelial cells exposed to glucose or activated for Arg1 upregulation by adenoviral delivery; Arg1-deficient mouse model	↑ Arg1	Glucose treatment activates Rho-associated protein kinases, which induce macrophages to upregulate Arg1	Substrate depletion by Arg1 reduces NO• and leads to impaired vascular relaxation, increased blood flow, and upsurge of reactive oxygen species, which causes premature endothelial cell senescence and defective vascular repair	[58]
	Diabetic mouse model; blood samples from diabetic patients		Increased plasma glucose levels induce the release of Arg1 via serum exosomes		[59]
	Mice induced to diabetes by streptozotocin; bovine retinal endothelial cells		High glucose levels activate NOX2 leading to upregulated Arg1		[60]
Obesity-induced vasculo-pathy	Diet-induced obesity and metabolic syndrome mouse model	↑ Arg1	High-fat, high-sucrose treatment activates Rho-associated protein kinases, which increases Arg1 expression	Upregulated synthesis of polyamines by Arg1 promotes cell proliferation and fibrosis; increased levels of reactive oxygen species contribute to dysfunction	[61]
Arterial thickening, fibrosis, and stiffening	Arg1-deficient mouse model; rat aortic smooth muscle cells	↑ Arg1	Angiotensin II acts upon the renin–angiotensin system and induces arginase upregulation	Enhanced synthesis of polyamines/proline leads to vascular cell proliferation and collagen formation, which changes smooth muscle tone	[62]
Hyper-tension	Obese and lean male rat models	↑ Arginase1	Obesity-induced arginase upregulation	L-Arginine depletion reduces NO•-mediated arterial vasodilation	[63]
Arterio-genesis	Male mice submitted to peripheral arteriogenesis; mouse primary artery endothelial cells and smooth muscle cells	↑ Arg1	Shear stress induces monocytes maturation to macrophages, which impairs M1/M2 to favor Arg1 expression	Enhanced Arg1 activity promotes perivascular M2 macrophage accumulation, which contributes to cell proliferation	[64]
Myocardial infarction	Male mouse submitted to surgical ligation of the left anterior descending coronary artery to induce myocardial infarction	↑ Arg1	Neutrophils are recruited and infiltrate into the infarcted area, activating the macrophages to favor Arg1 expression	Increased Arg1 activity results in enhanced proline and collagen synthesis, leading to fibrosis, ventricular remodeling, and eventual heart failure	[65]
Erectile dysfunction	Patients with a medical diagnosis of erectile dysfunction	↑ Arg1 and Arg2	Genetic polymorphisms induce Arg1 and Arg2 expression and activity	L-Arginine depletion leads to endothelial dysfunction and impaired smooth muscle relaxation; erectile dysfunction is an early sign of cardiovascular diseases	[66]
Chronic obstructive pulmonary disease	Ex vivo pulmonary vascular tissue from smokers	↑ Arg1	Tobacco smoking upregulates the arginase pathway	Imbalance of polyamines/NO• causes vascular remodeling, airway dysfunction, and oxidative stress	[67]
Pulmonary hypertension	Human pulmonary artery smooth muscle cell	↑ Arg2	Induced hypoxia activates protein kinases and transcription factors leading to the upregulation of Arg2 expression	Increased synthesis of polyamines leads to vascular smooth muscle cell proliferation and remodeling; decreased NO• synthesis impairs vasodilation, which contributes to dysfunction and pulmonary hypertension	[68]
	Human pulmonary artery smooth muscle cell; male mice exposed to hypoxia				[69]
Pulmonary fibrosis	Male mice with bleomycin-induced pulmonary fibrosis	↑ Arg2	Pro-inflammatory T helper cells change M1/M2 polarization and increase Arg2 expression	Increased biosynthesis of polyamines and collagen activates lung fibroblast proliferation and differentiation	[70]
	Primary bronchial cultures from cystic fibrosis patients	↑ Arginase1	F508del gene mutation leads to excessive arginase activity in the pulmonary tissue	Increased arginase expression results in a build-up of fibrotic mass; a decrease of NO• levels induces the deregulation of epithelial fluid transport in the lungs and reduce cilia motility	[71]
	Cystic fibrosis pediatric patients			High levels of arginase promote collagen deposition and NOS uncoupling, causing oxidative stress and tissue damage	[72]
	Cystic fibrosis patients	↑ Arg1	Recessive gene mutation leads to an excessive arginase activity in pulmonary tissue	Reduced NO• impairs smooth muscle relaxation, bronchodilation, and bacterial killing mechanisms	[73]
Asthma	Asthmatic patients	↑ Arg1	Allergen activation of IgE leads to neutrophil infiltration in lungs and activation of M2 arginase-expressing macrophages	Upregulation of Arg1 increases mucus production and smooth muscle contraction. Arg1 seems to correlate to bronchial asthma	[74]
		↑ Arg2	Chronic airway inflammations have high co-expression of Arg2 and iNOS	Arg2 delivers L-ornithine into mitochondria, providing nitrogen to an autonomous L-arginine-NO•-citrulline cycle and sustaining high NO• levels, which seems related to more severe and reactive conditions	[75]
	Human bronchial epithelial cell line (BET1A); Arg2-deficient mice with allergen-induced asthma	↑ Arg2	Allergens enhance hypoxia-induced factors, which activate IL-13 to upregulate Arg2	Increased Arg2 is suggested to be a counter-regulatory mechanism to reduce signal transduction and suppress airway inflammation	[76]
	Mite-challenged NC/Nga mouse model of asthma	↑ Arg1	Allergen activation induces the expression of arginase-upregulating mechanisms	Arginase decreases NO• levels, suppressing anti-inflammatory, bronchodilatory, and vascular modulating effects	[77]
Chronic rhino-sinusitis	Fragments of mucosa collected from the ethmoid sinus of chronic rhinosinusitis patients	↑ Arg2	Several cytokines found in the sinus mucosa lead to enhanced arginase expression	Increased Arg2 leads to cell and collagen proliferation and decreases NO• levels, which suppresses bronchodilatory and anti-inflammatory effects	[78]
Tuberculosis	Tissue samples from active tuberculosis patients; mouse model infected with Mycobacterium tuberculosis	↑ Arg1	Intracellular parasites circumvent NO• toxicity through the induction of Arg1-expressing macrophages in lungs	High Arg1 expression leads to collagen deposition and lung damage, which drives to inflammation by inhibiting type 1 helper T cells	[79]
Inflammatory bowel disease	Mouse model of inflammatory bowel disease by dextran sulfate sodium induction	↓ Arg1	Extracellular matrix protein 1 (ECM1) in macrophages impairs M1/M2 polarization decreasing the expression of Arg1	Reduction of Arg1 suppresses tissue repair mechanisms and, together with upregulated expression of inflammatory cytokines, increases chronic inflammatory response	[80]
Autoimmune (type 1) diabetes	Diabetic female mouse model induced by hyperglycemia	↑ Arg1	Increased plasma glucose levels impair M1/M2 polarization	Decreased NO• levels lead to a pro-inflammatory effect, weakening innate immunity	[81]
Arthritis	Synovial tissue samples from rheumatoid arthritis patients; arthritis mouse model (K/BxN)	↓ Arg1	Transcription factor Fos-related antigen 1 downregulate Arg1 expression by binding to the promoter region	Reduction of Arg1 suppresses polyamines synthesis and subsequently downregulates tissue repair mechanisms and counter-regulates pro-inflammatory cytokines	[82]
Multiple sclerosis	Arg2-knockout mice with induced autoimmune encephalomyelitis	↑ Arg2	Impaired M1/M2 macrophage polarization	Upregulated Arg2 stimulates the production of T helper 17 cells-differentiating cytokines, which induces inflammation	[83]
Viral infection	Patients with severe fever and thrombocytopenia syndrome	↑ Arg1	Viral-induced impairment of M1/M2 polarization favors the upregulation of Arg1	Arg1 causes L-arginine deficiency, which is associated with decreased NO• and suppresses antiviral immunity	[84]
	Mice infected with Trypanosoma cruzi and Schistosoma mansoni				[85]
	Peripheral lymph node cells from HIV patients				[86]
Peritonitis	Murine macrophage-like cell line (RAW264.7) and human monocyte cell line (THP-1)	↑ Arg1	IL-4-stimulated inflammation upregulates cytochrome P450 1A1, which impairs M1/M2 polarization	Increased Arg1 expression is associated with compensatory response mechanisms against an uncontrolled inflammation	[87]
Acute myeloid leukemia	Human acute myeloid leukemia cell lines (THP-1, U937, MOLM16, K562)	↑ Arg2	Increased acute myeloid leukemia blast cells overexpressing Arg2	Arg2 activity reduces IFN-γ and inhibits T cell immune-suppressive response	[88]
Chronic myelo-monocytic leukemia	Human bone marrow mononuclear cells	↑ Arg1	Mutations in epigenetic regulators upregulate Arg1	L-Arginine depletion by Arg1 suppress T-cells and contributes to immune evasion	[89]
Basal-like breast cancer	Human mammary epithelial cells (HeLa, HMEC, HMEC-ras, MDA-MB-231, MDA-MB-468)	↑ Arg2	Oncogene transformations trigger Arg2 expression	Arg2 upregulated between DNA synthesis and mitotic phases of cancer cells cycle promotes cell proliferation	[90]
Neuro-blastoma	Neural crest cell line (R1113T); neuroblastoma cell lines (SKNAS, KELLY, LAN-1, IMR-32,); Ewing’s sarcoma cell line (SKNMC); sympathetic ganglion-derived stem cells (SZ16)	↑ Arg2	IL-1β and TNF-α established a feedback loop to upregulate Arg2 expression via p38 and extracellular regulated kinases signaling	Arg2 induces cell proliferation and an immunosuppressive microenvironment due to inhibition of T cell cytotoxicity	[91]
Pancreatic ductal adeno-carcinoma	Human pancreatic ductal adenocarcinoma cell lines (AsPC-1, HPAC, MIA PaCa-2, PANC-1, SUIT-2, PA-TU-8988T); Arg2-deficient mouse pancreatic ductal adenocarcinoma cell lines	↑ Arg2	Arg2 is increased upon obesity and as a result of activating oncogenic mutations	Tumors (but not cultured cancer cells lacking the in vivo tumor microenvironment) need arginase to dispose of the excess of nitrogen accumulated to enhance tumorigenicity	[92]
Melanoma	Patient with metastatic L-arginine auxotrophic melanoma	↑ Arg2	Defects in the expression of OTC and ASS enzymes result in a dependence of extracellular L-arginine; counter-regulatory mechanisms lead to the upregulation of Arg2	Tumor cells were shown to be auxotrophic and avid for L-arginine to keep cell proliferation; high expression of Arg2 is induced to increase catalytic efficiency	[93]
	Human melanoma cell lines from patients with melanoma metastasis adhered to confluent human umbilical vein endothelial cells layers		Pro-inflammatory T helper cells change M1/M2 polarization and increase Arg2 expression	Arg2 enhances melanoma cell proliferation through polyamine production and promotes metastasis through enhancing H2O2 production and STAT3 signaling	[94]
Ovarian carcinoma	Human ovarian cancer cell lines (OVP-10, AD-10, A2780, Skov3, CaOv-3, MDAH2774, OvCa-14)	↑ Arg1	Tumor-derived exosomes containing Arg1 are released into circulation	Increased Arg1 expression inhibits antigen-specific T-cell proliferation and is related to a worse prognosis	[95]
Osteosarcoma	Human osteosarcoma cell lines (SaOS-2 and OS-17)	↑ Arg2	Hypoxic environment upregulates Arg2	Arg2 induces immunosuppression by inhibition of T-cells function	[96]
Glioma	Mouse glioma cell lines (GL261, KR158B)	↑ Arg1	Myeloid-derived suppressor cells overexpressing Arg1 infiltrate into the tumor	Increased Arg1 expression suppresses the efficacy of the immune system	[97]
Hepato-cellular carcinoma	Human hepatocellular carcinoma cell line (Huh7)	↑ Arg1	Impaired M1/M2 polarization induces Arg1 upregulation	Overexpression of Arg1 promotes cell proliferation, migration, and invasion, being a critical process in cancer metastasis and progression	[98]
	Patients with advanced hepatocellular carcinoma		Deprivation of L-arginine recycling enzymes OTC and ASS at the transcription or translational level	Tumor auxotrophic for L-arginine to enable cell proliferation and viability; L-arginine deprivation therapy can be a therapeutic approach	[99]
Cervical cancer	Human squamous cell carcinoma cells from patients	↑ Arginase1	Increased levels of circulating IL-10 and decreased levels of IFN-γ enhance arginase activity	Upregulated arginase levels contribute to the tumor immunosuppressive microenvironment	[100]
Alzheimer	Alzheimer’s disease mouse models	↑ Arg1 and Arg2	Microglial activation results in cytokines production, which induces the expression of arginase in brain	Arginase overexpression at β-amyloid deposition sites leads to NOS uncoupling, O2•− generation, and neuro-degenerative oxidative stress	[101]
Acute traumatic brain injury	Male rats submitted to traumatic brain injury surgery	↑ Arg1	Elevation of pro-inflammatory cytokines induces Arg1 expression	Increased Arg1 leads to eNOS uncoupling and enhances oxidative stress, inflammation, and vascular dysfunction	[102]
Fronto-temporal dementia	Male transgenic mice expressing a mutant form of human microtubule-associated protein tau	↑ Arginase1	Mutations in microtubule-associated protein tau	Functional significance of arginase remains uncertain as the production of polyamines enhances microtubule stability, which should reduce inflammation and tau proteins	[103]
Neuro-degeneration and neuro-vascular permeability	Male mice treated with homocysteine to induce vascular dysfunction and stroke-like symptoms	↓ Arginase1	Elevated levels of homocysteine, produced from methionine, lead to hyperhomocysteinemia, impairing NOS pathway	Upregulated NO• levels lead to nitrosative stress, extracellular matrix degradation, blood–brain barrier permeability, and neurodegeneration	[104]
Huntington’s disease	Post-mortem brain sections from patients with Huntington’s disease	↑ Arg1	Metabolic impairment of the urea cycle in the brain	Increased urea in the brain induces neurodegeneration by impaired osmoregulation	[105]
Acute ischemic stroke	Peripheral blood samples from patients with a first-ever acute ischemic stroke	↑ Arg1	Stroke induces the downregulation of a microRNA, which upregulates the Arg1 expression	Increased Arg1 acts against the activation of pro-inflammatory signals after stroke but may also be implicated in stroke-induced immunosuppression	[106]
Cerebral ischemia and excitotoxicity	Arg2-knockout mice with permanent distal middle cerebral artery occlusion or induced excitotoxicity	↓ Arg2	Arg2 deficiency worsens brain injury after an ischemic event	Arg2 may play a substantial protective role by regulating NO• levels and controlling reactive species	[107]

↑ increased levels; ↓ decreased levels; ¹ unspecified arginase isoform.