The immunomodulatory effect of hydroxytyrosol

Hydroxytyrosol (HT), a natural phenolic antioxidant, exerts immunomodulatory effects involving various immune cells, with particularly significant impacts on the functional regulation of T cells and macrophages. This regulation is not a simple "enhancement" or "inhibition" but rather a precise modulation of cell differentiation, cytokine secretion, and signaling pathways to maintain immune homeostasis. It can both strengthen protective immunity (such as anti-infection and anti-tumor responses) and inhibit excessive immune responses that cause inflammation or autoimmune damage. The specific mechanisms are elaborated below from the perspectives of T cells and macrophages:

I. Immunomodulatory Effects on T Cells

T cells are core cells of adaptive immunity, including subsets such as helper T cells (Th), regulatory T cells (Treg), and cytotoxic T cells (Tc, i.e., CD8⁺ T cells). The balance of their functions directly affects the direction and intensity of immune responses. HT’s regulation of T cells mainly manifests in the following aspects:

Regulating T cell subset differentiation to maintain immune balance

Th1/Th2 balance: Th1 cells primarily secrete cytokines such as IFN-γ and TNF-α, mediating cellular immunity (e.g., against intracellular pathogens and tumors); Th2 cells secrete IL-4, IL-5, etc., involved in humoral immunity (e.g., against parasites and allergic reactions). HT can inhibit excessive Th2 polarization (e.g., reducing IL-4 secretion) or slightly enhance IFN-γ production when Th1 function is insufficient, avoiding pathological states caused by immune bias (such as allergies or chronic infections).

Inhibiting excessive activation of Th17 cells: Th17 cells secrete IL-17, IL-22, etc., playing a key role in clearing extracellular pathogens and autoimmune diseases, but their overactivation can trigger chronic inflammation such as rheumatoid arthritis and psoriasis. HT can downregulate key transcription factors for Th17 differentiation (e.g., RORγt) and reduce IL-17 secretion, thereby inhibiting excessive inflammatory responses.

Promoting Treg cell function: Treg cells maintain immune tolerance and prevent autoimmunity by secreting inhibitory cytokines such as IL-10 and TGF-β. HT can upregulate the expression of Treg-specific surface molecules (e.g., Foxp3) and enhance their inhibitory effects. For example, in autoimmune disease models, HT pretreatment can reduce the attack of effector T cells on tissues.

Enhancing the killing function of cytotoxic T cells (Tc)

Tc cells recognize antigen-MHC class I molecule complexes on target cells (e.g., virus-infected cells, tumor cells) and release perforin, granzyme, etc., to induce target cell apoptosis. HT can improve the metabolic state of Tc cells (e.g., reducing oxidative stress-induced damage to mitochondrial function) or upregulate the expression of their surface TCR (T cell receptor) and CD8 molecules, enhancing their efficiency in recognizing and killing target cells. This role has potential value in anti-tumor and anti-viral immunity.

II. Immunomodulatory Effects on Macrophages

Macrophages are key cells of innate immunity, with functions including phagocytosis of pathogens, antigen presentation, and cytokine secretion. Their phenotypic polarization (M1 pro-inflammatory / M2 anti-inflammatory) is a core link in immunoregulation. HT’s regulation of macrophages mainly focuses on phenotypic switching and functional balance:

Inhibiting the pro-inflammatory activity of M1-type macrophages

M1-type macrophages are activated by pathogen stimulation (e.g., LPS, IFN-γ) and secrete large amounts of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and inflammatory mediators (e.g., NO, ROS). While effective in clearing pathogens, their overactivation can cause tissue damage (e.g., sepsis, chronic inflammation). HT inhibits M1 polarization through the following mechanisms:

Blocking the TLR4/NF-κB pathway: Pathogen-associated molecular patterns (PAMPs) such as LPS activate the TLR4 receptor, triggering NF-κB nuclear translocation and initiating pro-inflammatory gene transcription. The phenolic hydroxyl groups of HT can inhibit the binding of TLR4 to ligands or directly suppress IκB kinase (IKK) activity, preventing NF-κB activation and reducing pro-inflammatory cytokine secretion.

Reducing oxidative stress products: The respiratory burst of M1-type macrophages produces large amounts of ROS, exacerbating inflammation. As a strong antioxidant, HT can directly scavenge ROS or upregulate the expression of antioxidant enzymes (e.g., HO-1, Nrf2), reducing oxidative stress-induced overactivation of macrophages.

Promoting the anti-inflammatory and repair functions of M2-type macrophages

M2-type macrophages mainly secrete anti-inflammatory factors such as IL-10 and TGF-β, participating in tissue repair, immune regulation, and inflammation resolution after pathogen clearance. HT promotes M2 polarization through the following ways:

Activating the STAT6 pathway: Cytokines such as IL-4 and IL-13 can activate STAT6, inducing the expression of M2-type markers (e.g., CD206, Arg-1). HT can enhance STAT6 phosphorylation, promoting this process and accelerating inflammation resolution.

Enhancing phagocytic function: The phagocytic capacity of M2-type macrophages (e.g., clearing apoptotic cells and foreign bodies) is the basis for their repair role. HT can upregulate the expression of phagocytosis-related receptors (e.g., SR-A, CD36), enhancing macrophages’ efficiency in clearing pathogens or damaged cells and reducing triggers for persistent inflammation.

III. Summary: Core Logic of HT’s Immunomodulation

The essence of hydroxytyrosol’s regulation of T cells and macrophages is to achieve immune homeostasis through "balance" rather than "one-way regulation". For T cells, it inhibits overactivated effector subsets (e.g., Th17) while enhancing the functions of protective subsets (e.g., Tc, Treg). For macrophages, it suppresses M1-type pro-inflammatory damage and promotes M2-type anti-inflammatory repair, avoiding excessively strong or weak immune responses. This multi-targeted, bidirectional regulatory characteristic gives it broad application potential in fields such as anti-infection, anti-inflammation, autoimmune diseases, and tumor immunity.