The regulatory role of L-Arginine in autoimmune diseases

L-Arginine is a semi-essential amino acid with multiple biological functions. As a precursor of bioactive substances such as nitric oxide (NO), polyamines, and urea, it participates in regulating key physiological processes including immune cell activation, inflammatory responses, and vascular homeostasis. The core pathological mechanism of autoimmune diseases lies in immune system imbalance—the abnormal activation of autoreactive T/B cells, breakdown of immune tolerance, and excessive secretion of inflammatory cytokines, which in turn attack the body’s own tissues and organs. Through regulating immune cell metabolism, remodeling the immune microenvironment, and inhibiting abnormal inflammatory responses, L-Arginine exerts a bidirectional regulatory effect on autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Its effects are characterized by significant dose dependence and cell specificity.

I. Core Mechanisms of L-Arginine in Regulating Autoimmunity

The metabolic pathways of L-Arginine in the body determine its immunomodulatory functions, which are mainly exerted through two pathways: the nitric oxide synthase (NOS) pathway and the arginase pathway. The balance between these two pathways directly affects the functional orientation of immune cells.

Regulating Immune Cell Metabolism and Functional DifferentiationThe activation and differentiation of immune cells are highly dependent on metabolic reprogramming. As a key metabolic substrate, L-Arginine exerts a decisive influence on the functions of T cells, macrophages, and dendritic cells.

T Cell Regulation

The proliferation of effector T cells (e.g., Th1, Th17 cells) requires a large amount of L-Arginine as a raw material for protein synthesis, while maintaining their activated state relies on low concentrations of NO. In contrast, the differentiation of regulatory T cells (Treg cells) is promoted by high concentrations of NO—NO can activate the transcription factor Foxp3 in Treg cells, enhance their immunosuppressive function, and thereby inhibit the excessive proliferation of autoreactive T cells. In autoimmune diseases, the body exhibits L-Arginine metabolic disorders: high arginase expression leads to local L-Arginine depletion, which impairs the function of effector T cells due to insufficient metabolic substrates; meanwhile, Treg cell differentiation is blocked, further disrupting immune tolerance. Exogenous supplementation of L-Arginine can reverse this state, restore the suppressive function of Treg cells, and provide metabolic support for effector T cells to avoid excessive immunosuppression.

Macrophage Polarization

The phenotypes of macrophages (pro-inflammatory M1 type / anti-inflammatory M2 type) are closely related to autoimmune inflammation. High concentrations of NO generated from L-Arginine catalyzed by inducible nitric oxide synthase (iNOS) can inhibit the secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by M1 macrophages. Meanwhile, it promotes the polarization of M2 macrophages, which secrete anti-inflammatory cytokines including transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), alleviating tissue inflammatory damage. For example, in the synovial tissue of rheumatoid arthritis, L-Arginine supplementation can reduce M1 macrophage infiltration and relieve synovial hyperplasia and cartilage destruction in joints.

Dendritic Cell (DC) Function Regulation

Dendritic cells act as a bridge linking innate and adaptive immunity. In autoimmune diseases, DC cells exhibit abnormally enhanced capacity to present self-antigens, leading to the activation of autoreactive T cells. NO produced by L-Arginine metabolism can inhibit the maturation and antigen-presenting function of DC cells, reduce their ability to stimulate T cell activation, and thus decrease the initiation of autoimmune responses.

Inhibiting Abnormal Inflammatory Responses and Tissue DamageA typical feature of autoimmune diseases is the persistent activation of chronic inflammation. The cytokine storm and oxidative stress together cause tissue and organ damage, and L-Arginine inhibits this process through multiple pathways.

NO-Mediated Anti-Inflammatory Effects

Low to moderate concentrations of NO can inhibit the activation of the nuclear factor-κB (NF-κB) pathway, which is the core transcription factor regulating the expression of pro-inflammatory cytokines. Its inhibition reduces the secretion of inflammatory cytokines such as TNF-α, IL-6, and IL-17, alleviating inflammatory attacks on tissues such as joints, kidneys, and skin.

Antioxidative Stress Protection

In autoimmune diseases, excessive production of reactive oxygen species (ROS) exacerbates tissue oxidative damage. L-Arginine can promote the synthesis of glutathione—the body’s main antioxidant—and scavenge excess ROS. Meanwhile, NO can react with ROS to form peroxynitrite anions, reducing the cytotoxicity of ROS and protecting vascular endothelial cells and parenchymal organ cells.

Regulating Vascular Permeability

Autoimmune inflammation is often accompanied by vascular endothelial damage and increased permeability, leading to the extravasation of inflammatory cells and immune complexes into the interstitial space. NO generated from L-Arginine metabolism can dilate blood vessels, stabilize the junctions between vascular endothelial cells, reduce vascular permeability, and alleviate tissue damage caused by immune complex deposition (e.g., renal damage in systemic lupus erythematosus).

Regulating Intestinal Barrier Function and Improving the Immune MicroenvironmentThe intestine is the body’s largest immune organ. Impaired intestinal barrier function (“leaky gut”) allows undigested food antigens and intestinal flora to translocate into the bloodstream, triggering autoimmune responses. L-Arginine maintains the intestinal barrier in two ways:

It promotes the proliferation and repair of intestinal mucosal cells, enhances the expression of tight junction proteins (e.g., occludin, claudin), and reduces intestinal permeability.

It regulates the balance of intestinal flora, promotes the proliferation of beneficial bacteria such as Bifidobacterium and Lactobacillus, inhibits the growth of harmful bacteria, and reduces immune disorders caused by dysbiosis.

Clinical studies have shown that after L-Arginine supplementation, patients with rheumatoid arthritis exhibit significant improvements in intestinal barrier function indicators (e.g., serum endotoxin levels), along with alleviation of joint inflammatory symptoms.

II. Application Potential of L-Arginine in Common Autoimmune Diseases

Rheumatoid Arthritis (RA)The core pathology of rheumatoid arthritis involves synovial inflammation and cartilage and bone tissue destruction. The regulatory effects of L-Arginine are reflected in:

Inhibiting the activation of M1 macrophages and Th17 cells in synovial tissue, reducing the secretion of pro-inflammatory cytokines such as IL-17 and TNF-α, and alleviating joint swelling and pain.

Promoting Treg cell proliferation, enhancing their inhibitory effect on autoreactive T cells, and delaying disease progression.

Improving local blood circulation in joints, reducing immune complex deposition, and protecting chondrocytes.

Animal experiments have demonstrated that supplementing L-Arginine in rheumatoid arthritis model mice can significantly reduce arthritis scores and decrease the area of joint cartilage damage.

Systemic Lupus Erythematosus (SLE)Systemic lupus erythematosus is characterized by the production of autoantibodies and immune complex deposition, involving multiple systems such as the kidneys, skin, and blood. The roles of L-Arginine include:

Inhibiting the excessive activation of B cells, reducing the production of autoantibodies such as antinuclear antibodies, and decreasing immune complex formation.

Protecting renal vascular endothelial cells, reducing immune complex deposition in glomeruli, and alleviating proteinuria symptoms in lupus nephritis.

Regulating the balance of T cell subsets, increasing the proportion of Treg cells, and mitigating systemic inflammatory responses.

It should be noted that patients with lupus nephritis are often accompanied by renal function impairment, so L-Arginine supplementation requires strict dosage control to avoid increasing the metabolic burden on the kidneys.

Multiple Sclerosis (MS)Multiple sclerosis is an autoimmune disease of the central nervous system, pathologically characterized by demyelination and neuroinflammation. The regulatory value of L-Arginine lies in:

Promoting the polarization of microglia in the central nervous system toward the M2 type, inhibiting the destruction of myelin sheaths by inflammatory cytokines.

The generated NO can dilate cerebral blood vessels, improve blood supply to neural tissues, and promote myelin repair.

Regulating peripheral T cell subsets, reducing the infiltration of autoreactive T cells into the central nervous system across the blood-brain barrier.

Sjögren’s Syndrome (SS)Sjögren’s syndrome is mainly characterized by damage to exocrine glands such as salivary glands and lacrimal glands. L-Arginine can:

Promote the repair of salivary gland and lacrimal gland epithelial cells, improve glandular secretory function, and alleviate symptoms of dry mouth and dry eyes.

Inhibit chronic inflammatory infiltration in glandular tissues, reducing the destruction of glands caused by lymphocyte aggregation.

III. Application Precautions and Research Controversies

Dose Dependence: The Key to Bidirectional EffectsThe immunomodulatory effect of L-Arginine exhibits a dose-window effect, where different doses may produce diametrically opposite results:

Low to moderate doses (5–15 g daily): Mainly promote Treg cell differentiation, inhibit pro-inflammatory cytokine secretion, exert anti-inflammatory and immunosuppressive effects, and are suitable for adjuvant treatment of autoimmune diseases.

High doses (> 20 g daily): Excessive L-Arginine is catalyzed by iNOS to generate large amounts of NO, which may trigger adverse reactions such as vasodilation and hypotension. Meanwhile, high concentrations of NO may damage normal tissue cells and even exacerbate immune disorders.

Therefore, clinical application requires formulating personalized dosage regimens based on disease type and individual patient differences.

Contraindications and Populations Requiring Caution

Patients with hepatic or renal insufficiency: The liver is the main organ for L-Arginine metabolism, and the kidneys are responsible for excreting metabolic products. Supplementation in patients with hepatic or renal dysfunction may lead to elevated blood ammonia, azotemia, and increased burden on the organs.

Patients with concurrent infections: Excessive L-Arginine may inhibit the antibacterial activity of immune cells and increase the risk of infection spread.

Patients with bleeding tendency: NO has vasodilatory and platelet aggregation-inhibiting effects, which may increase bleeding risk.

Research Controversies: Balancing Efficacy and SafetySome studies suggest that exogenous L-Arginine supplementation may provide metabolic substrates for autoreactive immune cells, theoretically carrying the risk of promoting immune responses. However, more preclinical and clinical studies have shown that when used in combination with immunosuppressants, low to moderate doses of L-Arginine exert dominant anti-inflammatory and immunomodulatory effects, which can significantly enhance therapeutic efficacy and reduce the side effects of immunosuppressants (e.g., myelosuppression, gastrointestinal damage). Currently, the core of the controversy lies in the optimal dosage, administration timing, and synergistic regimens with traditional drugs for different autoimmune diseases.

Through regulating immune cell metabolism, inhibiting abnormal inflammation, and maintaining intestinal barrier function, L-Arginine plays an important bidirectional regulatory role in autoimmune diseases, providing new insights for the adjuvant treatment of these refractory diseases. The key to its application lies in precise dosage control and combined treatment strategies—combined use with traditional immunosuppressants and biological agents can not only enhance efficacy but also reduce drug side effects.