How does glutathione enhance immunity?

Glutathione (GSH) is a tripeptide (γ-L-glutamyl-L-cysteinyl-glycine) composed of glutamate, cysteine, and glycine, and is the most abundant non-protein thiol compound in mammalian cells.

It exists in two forms:

Reduced glutathione (GSH):

the main active form, provides reducing equivalents via its thiol group (-SH), directly neutralizing reactive oxygen species (ROS) such as H₂O₂, superoxide anion (O₂⁻), and hydroxyl radicals (•OH).

Oxidized glutathione (GSSG):

a dimer formed after GSH oxidation;

the GSH/GSSG ratio is a key indicator of cellular redox status.

Under normal physiological conditions, this ratio is >10:1;

a decrease indicates enhanced oxidative stress.

Synthesis and metabolic regulation

Synthesis pathway:

synthesized in the cytoplasm via two-step catalysis by glutamate-cysteine ligase (GCL) and glutathione synthetase;

cysteine is the rate-limiting substrate.

Regulatory factor:

nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator, upregulating expression of antioxidant genes such as GCL and glutathione peroxidase (GPx) by activating the antioxidant response element (ARE).

Intracellular transport:

Glutathione can be transported into mitochondria, nucleus, endoplasmic reticulum, and other organelles;

the liver is the main organ for Glutathione synthesis and export, and it can also be partially absorbed in the small intestine via diet (e.g., in small-peptide form).

Antioxidant and detoxification functions

Direct antioxidant:

reacts with ROS via its thiol group, reducing H₂O₂ to H₂O and scavenging lipid hydroperoxides (LOOH).

Enzymatic cofactor:

serves as a cofactor for GPx, promoting conversion of LOOH to non-toxic lipid alcohols (LOH);

via glutathione-S-transferase (GST), catalyzes detoxification of electrophiles (e.g., 4-hydroxy-2-nonenal).

Redox cycle maintenance:

GSSG is reduced back to Glutathione by glutathione reductase (GR) and NADPH, forming a redox cycle that maintains intracellular redox balance.

Regulatory roles of glutathione in immune responses

1. Effects on innate immunity

Innate immune cells (e.g., macrophages) produce ROS and cytokines (e.g., IL-12, IFN-γ) during antiviral responses;

Glutathione maintains intracellular redox balance, preserving macrophage metabolic activity and ROS scavenging capacity, preventing excessive oxidative stress damage.

For example, pro-inflammatory macrophages generate NADPH via the pentose phosphate pathway to maintain Glutathione in its reduced state, enhancing antioxidant capacity.

2. Modulation of adaptive immunity

Th1/Th2 balance regulation:

Glutathione levels directly affect helper T-cell (Th) differentiation.

High Glutathione promotes antigen-presenting cells (APCs, e.g., macrophages, dendritic cells) to secrete IL-12, favoring Th1-type immune responses (cell-mediated immunity, producing IFN-γ, IL-2);

Glutathione depletion reduces IL-12 secretion, shifting toward Th2-type responses (humoral immunity, producing IL-4, IL-6).

T-cell function maintenance:

Glutathione promotes T-cell proliferation, IL-2 secretion, and IL-2 receptor synthesis;

N-acetylcysteine (NAC, a Glutathione precursor) can restore T-cell IL-2 production impaired by oxidative stress.

3. Immune modulation during viral infections

Viral infections (e.g., HIV, influenza) deplete Glutathione;

possible mechanisms include:

cysteine is preferentially used for viral protein synthesis rather than Glutathione synthesis;

excessive ROS production accelerates Glutathione oxidation;

viral proteins (e.g., HIV Tat) inhibit Glutathione synthetase activity.

Glutathione suppresses nuclear factor-κB (NF-κB) activation, reducing release of virus-replication-associated cytokines (e.g., TNF-α, IL-6), and blocks NF-κB translocation to the nucleus, interfering with transcriptional activation of viruses such as HIV and HSV-1.

References

[1] Fraternale A, Paoletti M F, Casabianca A, et al. Glutathione and analogs in antiviral therapy[J]. Molecular aspects of medicine, 2009, 30(1-2): 99-110.

[2] Wróblewska J, Wróblewski M, Hołyńska-Iwan I, et al. The role of glutathione in selected viral diseases[J]. Antioxidants, 2023, 12(7): 1325.

*Special note - This article is for informational purposes only and cannot replace a doctor's treatment diagnosis and advice. It should not be regarded as a recommendation or proof of efficacy of the medical products involved. If it involves disease diagnosis, treatment, and rehabilitation, please be sure to go to a professional medical institution to seek professional advice.

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