The enhancing effect of L-Arginine on immune function

L-Arginine (L-Arg) is a semi-essential amino acid for humans. Under normal physiological conditions, the liver can synthesize sufficient L-arginine to meet the body’s needs. However, during immune stress (e.g., infection, trauma) or special physiological stages (e.g., infancy, old age), its synthesis becomes insufficient, requiring intake from foods (e.g., meat, fish, nuts) or supplements. Its molecular structure contains a guanidino group (-C(NH₂)₂⁺), making it a key precursor for synthesizing bioactive substances such as nitric oxide (NO), urea, and polyamines.L-Arginine plays a well-documented role in regulating immune cell activity, improving the immune microenvironment, and enhancing anti-infective capacity, earning it the title of the "core regulator of immune metabolism." This article systematically analyzes L-arginine’s immune-enhancing effects from three perspectives—immune cell regulation, immune effect mechanisms, and application scenarios—to provide a reference for its use in immune support.

I. L-Arginine’s Regulatory Effects on Core Immune Cells

The strength of immune function depends on the activity and quantity of immune cells (e.g., T cells, macrophages, natural killer cells). By providing metabolic substrates and regulating signaling pathways for immune cells, L-arginine directly enhances their proliferation capacity and effector functions—forming the core basis of its immune-enhancing effects.

(I) Activating T Lymphocytes: The "Core Executors" of Immune Responses

T cells are key cells of adaptive immunity, responsible for recognizing pathogens, eliminating infected cells and tumor cells. Their activation and proliferation require large amounts of energy and amino acid substrates. L-Arginine regulates T cell function through the following pathways:

Promoting T cell proliferation and differentiation: After activation, T cells enter a phase of rapid proliferation, which consumes large quantities of amino acids for protein and nucleic acid synthesis. As an essential amino acid,L-arginine directly participates in ribosome synthesis and DNA replication in T cells, significantly increasing their proliferation rate. In vitro experiments show that the number of proliferated T cells in culture systems supplemented with L-arginine is 2–3 times higher than that in non-supplemented groups. Additionally, L-arginine promotes the differentiation of naive T cells into effector T cells (e.g., Th1 cells that secrete interferon-γ) and memory T cells, enhancing long-term immune memory and reducing the risk of secondary infections.

Enhancing T cell cytotoxicity: Cytotoxic T lymphocytes (CTLs) lyse infected cells by releasing substances such as perforin and granzyme—a process that requires NO. L-Arginine is converted into NO in T cells under the action of inducible nitric oxide synthase (iNOS). NO enhances the membrane-penetrating ability of perforin and inhibits the metabolism of pathogens (e.g., viruses, bacteria) in infected cells, synergistically improving CTL killing efficiency. Studies have found that CTL killing activity decreases by more than 50% under L-arginine deficiency, but can be quickly restored after supplementation.

Alleviating T cell exhaustion: Chronic infections (e.g., chronic hepatitis B, tumors) can lead to T cell exhaustion (impaired function, increased expression of inhibitory surface receptors).L-Arginine alleviates exhaustion by inhibiting the activity of indoleamine 2,3-dioxygenase (IDO)—an immunosuppressive enzyme that depletes L-arginine in the microenvironment, causing T cell dysfunction due to amino acid deficiency. Supplementing L-Arg competitively inhibits IDO, maintains amino acid concentrations in the T cell microenvironment, and restores T cell activation ability.

(II) Enhancing Macrophage Function: The "Frontline of Innate Immunity"

Macrophages are core cells of innate immunity, responsible for phagocytosing pathogens, presenting antigens, and secreting cytokines. L-Arginine strengthens innate immune defense by regulating macrophage metabolic status and effector functions:

Promoting phagocytic and bactericidal abilities: After phagocytosing pathogens, macrophages kill them through "respiratory burst" (production of reactive oxygen species, ROS) and NO. As the only precursor of NO,L-arginine significantly increases NO production in macrophages. In vivo experiments show that in mice supplemented with L-arginine, macrophage NO concentration is 3–4 times higher than that in the control group, and the phagocytic and bactericidal rates against E. coli and Staphylococcus aureus increase by more than 60%. Additionally,L-arginine enhances the expression of phagocytic receptors (e.g., CD14) on the macrophage surface, further improving phagocytic efficiency.

Regulating cytokine secretion: Macrophages regulate immune responses by secreting cytokines (e.g., tumor necrosis factor-α, TNF-α; interleukin-6, IL-6). L-Arginine promotes macrophages to secrete pro-inflammatory cytokines (enhancing anti-infective immunity) while inhibiting excessive secretion of anti-inflammatory cytokines (e.g., IL-10) to avoid immune suppression. For example, in a pneumonia model, L-arginine supplementation doubles macrophage TNF-α secretion, accelerates bacterial clearance in the lungs, and shortens the infection course.

Inhibiting macrophage apoptosis: During infection or traumatic stress, macrophages are prone to apoptosis due to overactivation, weakening immune defense. L-Arginine inhibits the expression of macrophage apoptosis-related proteins (e.g., Caspase-3) by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, prolonging macrophage survival and maintaining sustained immune defense.

(III) Strengthening Natural Killer (NK) Cell Activity: The "Rapid Response Force" Against Tumors and Viruses

NK cells directly kill tumor cells and virus-infected cells without antigen stimulation, serving as the "rapid response cells" of innate immunity. L-Arginine enhances their effector functions through metabolic support and signal regulation:

Improving NK cell killing activity: NK cell killing relies on the release of cytotoxic granules (e.g., perforin, granzyme) and the synergy of NO. L-Arginine not only provides substrates for NO synthesis but also promotes granzyme synthesis in NK cells. Clinical studies show that after healthy adults supplement L-arginine (10 g per day for 7 consecutive days), the killing rate of NK cells against K562 tumor cells increases from 35% to 60%, and this killing activity can last for 1–2 weeks.

Promoting NK cell proliferation and migration: Under stress (e.g., surgery, infection), the number of NK cells tends to decrease.L-Arginine activates the mammalian target of rapamycin (mTOR) signaling pathway (regulating cell metabolism and proliferation), promoting NK cell migration from the bone marrow to infection sites or tumor tissues while increasing NK cell quantity. In a mouse tumor model,L-arginine supplementation triples the number of NK cells infiltrating tumor tissues, significantly inhibiting tumor growth.

II. Key Mechanisms of L-Arginine’s Immune-Enhancing Effects

L-Arginine’s regulatory effects on immune cells are essentially achieved through "metabolic pathway regulation" and "immune microenvironment improvement." The core mechanisms include three pathways—NO synthesis, energy metabolism support, and immunosuppressive factor antagonism—which work synergistically to form a complete immune-enhancing network.

(I) Nitric Oxide (NO) Synthesis Pathway: The "Core Mediator" of Immune Effects

Under the catalysis of nitric oxide synthase (NOS), L-Arg is converted into NO and citrulline. NO is a key mediator of immune enhancement, and its role runs through the entire process of immune cell activation, killing, and signal transmission:

On immune cells themselves: NO activates the intracellular cyclic guanosine monophosphate (cGMP) signaling pathway, promoting the activation and proliferation of immune cells (e.g., T cells, macrophages) while enhancing the activity of cytotoxic substances (e.g., perforin).

On pathogens: NO has strong oxidizing properties, which can damage bacterial cell membranes, inhibit viral nucleic acid replication (e.g., influenza virus, hepatitis B virus), and suppress key enzymes of pathogens (e.g., bacterial respiratory chain enzymes), leading to pathogen metabolic disorders.

On the immune microenvironment: NO dilates blood vessels, increasing the migration and infiltration of immune cells to infection sites. It also promotes the release of inflammatory factors (e.g., TNF-α), amplifying immune responses.

It should be noted that NO production is "cell-specific": Immune cells (e.g., activated macrophages, T cells) express inducible NOS (iNOS) and only synthesize large amounts of NO during immune activation; vascular endothelial cells express constitutive NOS (eNOS) and synthesize small amounts of NO under basal conditions to regulate vascular function. Through the substrate distribution of L-Arg, these two cell types maintain the balance between immune function and physiological function.

(II) Energy Metabolism Support Pathway: The "Material Basis" of Immune Cell Activation

Immune cell activation (e.g., T cell proliferation, macrophage phagocytosis) consumes large amounts of energy (mainly from glycolysis and oxidative phosphorylation). By regulating the metabolic status of immune cells, L-Arg provides them with energy and synthetic substrates:

Promoting glycolysis: Activated T cells and macrophages rely primarily on glycolysis for energy (the "Warburg effect").L-Arginine enhances the glycolytic rate of immune cells by activating hexokinase (a key glycolytic enzyme), increasing ATP production. In vitro experiments show that T cells treated with L-arginine have a 40% higher glycolytic rate and double the ATP concentration, meeting the energy needs of rapid proliferation.

Participating in protein synthesis: The proliferation and effector functions of immune cells depend on de novo protein synthesis (e.g., cytokines, receptors, cytotoxic granules). As an essential amino acid, L-arginine is a key raw material for protein synthesis, directly participating in amino acid chain elongation in ribosomes and improving the synthesis efficiency of immune-related proteins. For example, under L-arginine deficiency, macrophage TNF-α synthesis decreases by 70%, but can be restored to normal levels after supplementation.

Regulating polyamine synthesis: Under the action of arginine decarboxylase, L-arginine is converted into polyamines (e.g., putrescine, spermidine). Polyamines are important regulators of cell proliferation, promoting DNA replication and cell cycle progression to further support the proliferation and differentiation of immune cells.

(III) Immunosuppressive Factor Antagonism Pathway: The "Balancing Strategy" for Improving the Immune Microenvironment

Under pathological conditions (e.g., tumors, chronic infections), the body produces immunosuppressive factors (e.g., IDO, prostaglandin E₂, PGE₂) that deplete L-Arg or inhibit immune cell activity. Through "substrate supplementation" and "signal antagonism," L-Arginine breaks immune suppression and restores immune balance:

Antagonizing IDO-mediated immunosuppression: IDO is a major immunosuppressive enzyme in the tumor microenvironment and chronic infections. It decomposes L-arginine into kynurenine, leading to L-Arg deficiency in the local microenvironment and inhibiting T cell activation. Supplementing L-Arg competitively binds to IDO, reducing L-arginine depletion. It also increases local amino acid concentrations, restoring T cell proliferation and killing functions. In a melanoma model, the combination of L-arginine and PD-1 inhibitors reduces IDO activity by 50%, quadruples T cell infiltration, and significantly improves anti-tumor efficacy.

Inhibiting PGE₂-mediated immunosuppression: PGE₂ is an anti-inflammatory mediator; its excessive secretion inhibits the activity of macrophages and NK cells.L-Arginine reduces the expression of cyclooxygenase-2 (COX-2, a key enzyme in PGE₂ synthesis), lowering PGE₂ concentrations. It also enhances the secretion of pro-inflammatory cytokines (e.g., IL-12) to balance immune responses. In a sepsis model,L-arginine supplementation reduces PGE₂ concentrations in mice by 30%, restores NK cell activity to 80% of normal levels, and improves survival rates.

III. Application Scenarios and Precautions for L-Arginine’s Immune Enhancement

L-Arginine’s immune-enhancing effects have clear applications in clinical practice and daily health care, especially for populations with low immune function or under stress. However, it is necessary to follow reasonable dosages and usage guidelines to avoid potential risks.

(I) Main Application Scenarios

Adjuvant treatment of infectious diseases: In bacterial infections (e.g., pneumonia, urinary tract infections) and viral infections (e.g., influenza, COVID-19), supplementing L-arginine enhances the activity of macrophages and NK cells, accelerates pathogen clearance, and shortens the course of illness. Clinical studies show that mild COVID-19 patients supplemented with L-arginine (8 g per day for 14 consecutive days) have a 2–3 day shorter virus clearance time than the control group, with significantly lower levels of inflammatory factors (e.g., IL-6).

Perioperative immune support: Surgical trauma temporarily suppresses immune function (e.g., decreased T cell activity, weakened macrophage phagocytosis), increasing the risk of postoperative infections. Supplementing L-arginine (10–15 g per day) 3–5 days before surgery maintains T cell and NK cell activity, reduces the postoperative infection rate (e.g., from 25% to 10% in abdominal surgery patients), and promotes wound healing (polyamines support tissue repair).

Adjuvant tumor treatment: Tumor patients often experience immune suppression due to excessive IDO expression. Supplementing L-arginine enhances anti-tumor immunity, and its combination with immune checkpoint inhibitors (e.g., PD-1 antibodies) improves efficacy. Clinical data show that advanced lung cancer patients treated with a combination of L-arginine (12 g per day) and PD-1 inhibitors have an objective response rate increased from 20% to 35%, with no significant additional side effects.

Immune health care for special populations: Infants (especially premature infants with insufficient L-arginine synthesis ability), the elderly (with natural immune decline), and vegetarians (with low L-Arg content in plant-based diets) can supplement L-arginine daily (200–300 mg/kg for infants, 3–5 g for adults) to enhance immune function and reduce the incidence of diseases such as respiratory infections and diarrhea.

(II) Precautions and Safety Guidelines

Reasonable dosages and contraindicated populations:

The recommended daily dosage for healthy adults is 3–10 g (obtainable through food or supplements). Long-term high-dose intake (>20 g per day) may cause gastrointestinal discomfort (e.g., nausea, diarrhea) and hyperuricemia (L-Arg metabolism produces urea, increasing uric acid production).

Contraindicated populations include patients with severe liver or kidney dysfunction (impaired liver urea synthesis leading to ammonia toxicity; impaired renal excretion causing amino acid accumulation), herpes virus (L-arginine may promote virus replication), and hypotensive patients (NO dilates blood vessels, potentially lowering blood pressure further).

Drug interactions:

When used in combination with antihypertensive drugs (e.g., calcium channel blockers, ACE inhibitors), monitor blood pressure to avoid hypotension risks.

When used with anticoagulants (e.g., warfarin), it may increase bleeding risks (NO inhibits platelet aggregation); regular monitoring of coagulation function is required.

When used with immunosuppressants (e.g., cyclosporine), it may antagonize immunosuppressive effects and affect the control of rejection after organ transplantation—concurrent use should be avoided.

Sources and supplementation methods:

Prioritize food-based supplementation. Foods rich in L-arginine include lean meat (beef, pork), fish (salmon, tuna), nuts (walnuts, almonds), legumes (soybeans, lentils), and dairy products. A balanced daily diet can meet basic needs.

For additional supplementation, choose L-arginine supplements (e.g., capsules, powders) from reputable brands to avoid purchasing inferior products (which may contain heavy metals or impurities). Before supplementation, consult a doctor or dietitian to develop a plan based on individual conditions.

By regulating the activity of core immune cells (e.g., T cells, macrophages, NK cells) and combining three mechanisms—NO synthesis, energy metabolism support, and immunosuppressive factor antagonism—L-arginine forms a multi-dimensional immune-enhancing network. It has clear application value in infection treatment, perioperative support, adjuvant tumor treatment, and health care for special populations. Its advantages lie in being a natural amino acid with high safety, good compatibility with the human body, and the ability to synergistically improve efficacy with conventional treatments (e.g., antibiotics, immunosuppressants). However, reasonable dosages and contraindicated populations should be noted to avoid blind supplementation. Future research can further focus on the synergistic effects of L-arginine with other immunomodulators (e.g., probiotics, vitamin D) and its precise application in specific diseases (e.g., autoimmune diseases) to further expand its application boundaries in the field of immunology.