L-Arginine and immune function

As a semi-essential amino acid in the human body, L-arginine can be synthesized by the body itself under normal physiological conditions. However, in special scenarios such as immune activation, stress, or disease, its synthesis cannot meet the demand, requiring exogenous supplementation. Its regulatory effect on immune function is not achieved through a single pathway; instead, it acts as a key metabolic substrate to participate in immune cell energy supply, synthesize immune-active molecules, and regulate immune cell differentiation and function, thereby exerting multi-dimensional impacts from the cellular level to the overall immune response. Relevant mechanisms have gradually transitioned from basic research to clinical application.

I. Basic Research: Core Mechanisms of L-Arginine Regulating Immune Function

At the molecular and cellular levels, L-arginine participates in immune function regulation primarily through three core metabolic pathways and direct regulation of immune cells, which form the biological basis for its effects.

(1) Serving as the Only Substrate for Nitric Oxide (NO) Synthesis to Regulate Immune Cell Killing and Vascular Function

L-arginine is the sole raw material for the synthesis of NO catalyzed by nitric oxide synthase (NOS), and NO is a key signaling molecule in the immune response, with its role spanning the entire process of immune defense:

Enhancing immune cell killing ability: In macrophages, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs), L-arginine is catalyzed by inducible nitric oxide synthase (iNOS) to produce large amounts of NO. NO can directly kill bacteria (e.g., Escherichia coli, Staphylococcus aureus), fungi (e.g., Candida albicans), and parasites (e.g., Toxoplasma gondii) by inhibiting the activity of pathogen respiratory chain enzymes and damaging pathogen DNA structures. Meanwhile, NO can promote the activation and proliferation of CTLs, enhancing their targeted killing effect on tumor cells or virus-infected cells.

Regulating immune-related vascular function: NO can relax vascular smooth muscle, increase blood flow to immune organs (e.g., lymph nodes, spleen), and promote the migration of immune cells (e.g., lymphocytes, macrophages) to inflammatory sites or infection foci. Additionally, NO can inhibit platelet aggregation, preventing local thrombus formation from obstructing immune cell transport and providing a favorable microenvironment for the immune response.

(2) Participating in the Urea Cycle and Polyamine Synthesis to Maintain Immune Cell Metabolism and Proliferation

L-arginine can be decomposed into ornithine under the catalysis of arginase (ARG), which is further converted into polyamines (e.g., putrescine, spermidine, spermine). This pathway is crucial for the survival and function of immune cells:

Supporting immune cell energy metabolism: Immune cells (especially activated T cells) experience a sharp increase in energy demand during proliferation. L-arginine participates in the tricarboxylic acid (TCA) cycle through the urea cycle to provide ATP for cells. Meanwhile, its metabolic intermediate α-ketoglutarate can act as a TCA cycle substrate to further enhance energy supply, preventing immune cell activation from being hindered due to insufficient energy.

Promoting immune cell proliferation and differentiation: Polyamines are key substances required for cell division, as they can stabilize DNA structure and promote ribosome assembly, supporting the rapid proliferation of immune cells (e.g., T cells, B cells). For example, during the differentiation of T cells into Th1 and Th2 subtypes, polyamines can regulate the expression of cell cycle-related proteins (e.g., Cyclin D1), driving cells from the G1 phase to the S phase and ensuring the generation of a sufficient number of effector cells in the immune response.

(3) Regulating Immune Cell Differentiation and Function to Reshape Immune Balance

L-arginine can regulate the differentiation direction and functional state of immune cells through direct or indirect effects, preventing the immune response from being excessively strong or weak:

Promoting the activation of effector immune cells: For naive T cells, L-arginine can activate the mammalian target of rapamycin (mTOR) signaling pathway—a core regulatory factor for cell metabolism and immune activation. Once activated, mTOR promotes the differentiation of T cells into CTLs with killing function or Th1 cells that secrete pro-inflammatory factors (e.g., IFN-γ, IL-2), enhancing the cellular immune response. Meanwhile, it can also improve the antibody secretion ability of B cells and promote the production of IgG and IgM in humoral immunity.

Inhibiting excessive proliferation of regulatory T cells (Treg): In immune homeostasis, Treg can inhibit excessive immune responses to avoid autoimmune damage. However, in infection or tumor scenarios, overactivation of Treg weakens the immune response. L-arginine can reduce the proliferation and immunosuppressive function of Treg by downregulating the activity of ARG (overexpression of ARG consumes local L-arginine, leading to T cell anergy), thereby restoring the killing activity of effector immune cells. This mechanism has received particular attention in tumor immunology research.

II. Clinical Application: Practice and Effects of L-Arginine in Immune-Related Scenarios

Based on the immune regulatory mechanisms clarified by basic research, L-arginine has been applied clinically in infectious diseases, adjuvant tumor therapy, perioperative immune protection, and immune improvement in special populations, with clear application consensuses formed in some scenarios.

(1) Infectious Diseases: Enhancing Immune Defense and Assisting in Infection Control

In scenarios where immune function is impaired due to infections by pathogens such as bacteria and viruses, exogenous supplementation of L-arginine can help improve infection prognosis by enhancing the killing ability of immune cells:

Bacterial infections: In patients with severe pneumonia, abdominal infections, and other conditions, infection is often accompanied by increased L-arginine consumption (activation of iNOS leads to increased NO synthesis, and elevated ARG activity accelerates L-arginine decomposition), resulting in an "arginine deficiency" state that further impairs immune cell function. Clinical studies have shown that supplementing L-arginine (10–20 g per day, orally or intravenously) on the basis of conventional anti-infective treatment can increase NO production by macrophages, NK cell activity, and the proportion of CTLs in the peripheral blood of patients, shorten the duration of fever, and reduce the mechanical ventilation rate and hospital stay of patients with severe infections. The effect is more significant in elderly or malnourished infected patients, as these populations have weaker intrinsic arginine synthesis capacity and are more prone to deficiency.

Viral infections: In viral diseases such as influenza and COVID-19, L-arginine exerts its effects in two ways: first, it enhances the recognition and killing of virus-infected cells by NK cells, reducing virus replication; second, it regulates the inflammatory response to avoid cytokine storms (NO can inhibit excessive release of pro-inflammatory factors while promoting the expression of the anti-inflammatory factor IL-10). Clinical observations have found that mild COVID-19 patients who supplemented L-arginine experienced faster relief of respiratory symptoms (e.g., cough, chest tightness) and shorter recovery time of peripheral blood lymphocyte count. However, more large-scale clinical trials are still needed to verify its effect in severe viral infections.

(2) Adjuvant Tumor Therapy: Improving the Immune-Suppressive Microenvironment and Enhancing Treatment Tolerance

Tumor patients often have an "immune-suppressive microenvironment" (e.g., excessive accumulation of Treg, elevated ARG activity leading to local L-arginine deficiency), and radiotherapy and chemotherapy further damage immune function. L-arginine can be used as an adjuvant to address this issue:

Enhancing the efficacy of immunotherapy: In the treatment with immune checkpoint inhibitors (e.g., PD-1/PD-L1 antibodies), some patients experience T cell anergy due to insufficient L-arginine in the tumor microenvironment, resulting in low treatment response rates. Supplementing L-arginine can increase the concentration of L-arginine in the tumor microenvironment, activate T cell activity, and enhance the anti-tumor effect of immune checkpoint inhibitors. Clinical studies have shown that melanoma and non-small cell lung cancer patients who supplemented L-arginine during immunotherapy had an objective response rate (ORR) increased by 15%–20% without additional adverse reactions.

Alleviating radiotherapy- and chemotherapy-related immune damage: Radiotherapy and chemotherapy inhibit bone marrow hematopoietic function, leading to decreased counts of white blood cells and lymphocytes and increased infection risk. L-arginine can promote the proliferation of bone marrow hematopoietic stem cells, increase the number of white blood cells (especially neutrophils) and lymphocytes in the peripheral blood, and reduce radiotherapy- and chemotherapy-induced immunosuppression. For example, colorectal cancer patients who supplemented L-arginine (15 g per day, orally) during chemotherapy had a 30% reduction in the incidence of neutropenia, a significant decrease in chemotherapy delay rate, and improved appetite and physical status.

(3) Perioperative Period: Protecting Immune Function and Reducing Postoperative Infection Risk

Surgical trauma triggers a stress response, leading to decreased immune cell activity (e.g., weakened phagocytic capacity of macrophages, inhibited T cell proliferation) and increased risk of postoperative infections (e.g., surgical site infection, pulmonary infection). L-arginine can exert a protective effect by regulating immune metabolism under stress:

Preoperative supplementation: For surgeries with significant trauma, such as gastrointestinal surgery and major orthopedic surgery, oral supplementation of L-arginine (10–15 g per day) 3–7 days before surgery can increase the activity of CTLs and NK cells in the peripheral blood of patients before surgery, enhance the body’s preoperative immune reserve, and lay the foundation for postoperative immune recovery.

Postoperative supplementation: Initiating L-arginine supplementation in the early postoperative period (1–2 days after surgery) can reduce the increase in ARG activity caused by surgical stress, avoiding local L-arginine deficiency. Meanwhile, its metabolite NO can improve intestinal mucosal blood flow, protect intestinal barrier function, and reduce postoperative infections caused by intestinal bacterial translocation. Clinical data show that supplementing L-arginine can reduce the postoperative surgical site infection rate of patients undergoing major abdominal surgery by 25%–30%, shorten the postoperative hospital stay by 1–2 days, and have no significant adverse effects on liver and kidney function.

(4) Special Populations: Improving Immune Deficiency and Maintaining Immune Homeostasis

For populations with weak intrinsic immune function (e.g., the elderly, malnourished individuals, patients with chronic kidney disease), L-arginine can be used as a nutritional supplement to improve immune function:

The elderly: With increasing age, the activity of arginine synthase in the human body decreases, and digestive and absorption functions weaken, easily leading to insufficient L-arginine intake and functional decline of immune cells (e.g., T cells, NK cells). Daily supplementation of 5–10 g of L-arginine can increase the lymphocyte transformation rate, IgG level, and NK cell killing activity in the peripheral blood of the elderly, reducing the incidence of respiratory tract infections and urinary system infections.

Patients with chronic kidney disease: Due to impaired renal function, patients with chronic kidney disease experience reduced L-arginine synthesis due to urea cycle disorders, and dialysis treatment accelerates its loss, resulting in immune insufficiency. Appropriate supplementation of L-arginine (5–8 g per day) under the guidance of a doctor can improve the immune cell activity of patients and reduce the risk of dialysis-related infections (e.g., catheter-related bloodstream infections). However, it is necessary to monitor blood ammonia levels to avoid ammonia poisoning caused by abnormal arginine metabolism.

III. Application Precautions and Future Directions

Although the role of L-arginine in immune regulation has been widely verified, attention must be paid to its safety and applicability in clinical practice, and future research needs to further break through key bottlenecks:

Dosage and individual differences: The immune regulatory effect of L-arginine is dose-dependent—too low a dose fails to exert effects, while an excessively high dose may cause gastrointestinal discomfort (e.g., abdominal distension, diarrhea) or metabolic abnormalities (e.g., elevated blood ammonia). Clinically, the dose needs to be adjusted according to the patient’s age, underlying diseases, and immune status (the conventional adult dose is 5–20 g per day). In addition, for patients with arginase deficiency or severe liver failure, strict prohibition or use under close monitoring is required to avoid accumulation of metabolites.

Potential for combined application: Current research has found that when L-arginine is used in combination with nutrients such as probiotics, vitamin C, and zinc, a "synergistic immune regulatory effect" can be produced. For example, L-arginine promotes NO synthesis, while probiotics optimize the intestinal microbiota; their combination can further enhance the intestinal immune barrier function. In the future, more combined regimens can be explored to improve clinical efficacy.

Deepening mechanisms and clinical evidence: Existing basic research has clarified the regulatory pathways of L-arginine on immune cells, but the specific differences in its effects across different diseases (e.g., autoimmune diseases, rare infections) still require in-depth study. Meanwhile, for complex scenarios such as severe infections and advanced tumors, large-scale, multi-center randomized controlled trials (RCTs) are still needed to verify its long-term efficacy and safety, providing more solid evidence support for clinical application.

The transformation of L-arginine from an "immune cell metabolic substrate" to a "clinical immunomodulator" reflects the close integration of basic research and clinical application. Through multi-pathway regulation of immune function, it has demonstrated clear value in scenarios such as infection control, adjuvant tumor therapy, and perioperative protection. However, further optimization in precise dosage, individual adaptability, and combined regimens is needed to better serve the clinical treatment of immune-related diseases.