The role of phospholipids in immune regulation

As a core component of biological membranes, phospholipids play a "dual role" in immune regulation—they can both initiate immune responses by activating inflammatory signaling pathways and mediate anti-inflammatory reactions through metabolites. The balance of their functions directly affects the maintenance of immune homeostasis. This duality stems from the structural diversity of phospholipid molecules and the complexity of their metabolic pathways, with specific manifestations as follows:

I. Pro-Inflammatory Effects of Phospholipids: The "Signal Switch" for Initiating Immune Defense

When pathogens invade or tissue damage occurs, phospholipids trigger inflammatory responses through the following pathways, activating the body’s anti-infection defense mechanisms:

Hydrolysis of membrane phospholipids and release of pro-inflammatory mediators

Activated phospholipases (e.g., phospholipase A₂, PLA₂) hydrolyze membrane phospholipids (such as phosphatidylcholine and phosphatidylinositol) to release arachidonic acid (AA) and lysophospholipids. AA is metabolized by cyclooxygenase (COX) or lipoxygenase (LOX) to generate pro-inflammatory mediators like prostaglandins (e.g., PGE₂) and leukotrienes (e.g., LTB₄). These molecules induce vasodilation, leukocyte chemotaxis (e.g., recruiting neutrophils to infection sites), and enhance local immune responses. For example, when macrophages are stimulated by bacterial lipopolysaccharide (LPS), PLA₂-mediated phospholipid hydrolysis increases significantly, driving the secretion of pro-inflammatory factors (e.g., TNF-α, IL-6) and initiating innate immunity.

Phospholipid derivatives as ligands for pattern recognition receptors (PRRs)

Certain phospholipid metabolites can directly activate PRRs on the surface of immune cells, amplifying inflammatory signals. For instance, lysophosphatidic acid (LPA) binds to G protein-coupled receptors (e.g., LPAR₁) to activate the NF-κB pathway, promoting dendritic cell maturation and cytokine release. Phosphatidylserine (PS), exposed on the cell membrane surface during apoptosis, is recognized by PS receptors on macrophages to initiate phagocytic clearance. However, in certain pathological conditions (e.g., tumor microenvironments), excessive PS can evade immune surveillance by inhibiting T cell activity, and its pro-inflammatory or anti-inflammatory effects depend on the cellular context.

II. Anti-Inflammatory Effects of Phospholipids: The "Regulator" for Terminating Excessive Inflammation

When overactivated inflammatory responses may cause tissue damage, phospholipids inhibit inflammation through metabolic shunting or direct action, maintaining immune balance:

Production of anti-inflammatory phospholipid metabolites

Another metabolic branch of phospholipids generates molecules with anti-inflammatory activity. For example, arachidonic acid is metabolized by cytochrome P450 enzymes to produce epoxyeicosatrienoic acids (EETs), which inhibit NF-κB activity, reduce pro-inflammatory factor release, and promote nitric oxide (NO) production in vascular endothelial cells to alleviate vasospasm. Phosphatidic acid (PA), generated by phospholipase D-mediated hydrolysis of phosphatidylcholine, can inhibit the conversion of macrophages from a pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2) by activating the AMPK pathway, thereby promoting tissue repair.

Regulation of immune cell function by phospholipids

Phospholipids exert anti-inflammatory effects by regulating the differentiation and function of immune cells. For example, ceramide, generated by sphingomyelin hydrolysis via sphingomyelinase, can induce T cell apoptosis, limiting excessive activation of adaptive immune responses. Phosphatidylinositol-3,4,5-trisphosphate (PIP₃) maintains the suppressive function of regulatory T cells (Treg) by regulating the PI3K/Akt pathway, inhibiting autoimmune inflammation. Additionally, exogenous phospholipids (e.g., phosphatidylethanolamine in fish oil) can reduce the sensitivity of immune cells to pro-inflammatory signals by affecting membrane fluidity, indirectly exerting anti-inflammatory effects.

III. Regulatory Mechanisms for Balancing Pro-Inflammatory and Anti-Inflammatory Effects: "Dynamic Switching" of Metabolic Pathways

The dual immunomodulatory effects of phospholipids are not isolated but achieve balance through dynamic regulation of metabolic networks:

Selective activation of enzymes: Phospholipases (e.g., different subtypes of PLA₂) primarily activate pro-inflammatory pathways in the early stages of inflammation, while in the late stages, anti-inflammatory-related phospholipid-metabolizing enzymes (e.g., cytochrome P450 producing EETs) are preferentially activated, shifting metabolic flux toward anti-inflammatory products.

Cell type specificity: The same phospholipid molecule may mediate opposite effects in different immune cells. For example, phosphatidylinositol (PI) promotes the secretion of inflammatory factors in macrophages but enhances immune suppressive function in Treg cells. This difference is related to the expression profile of intracellular signaling molecules.

Imbalance in pathological states: In diseases such as rheumatoid arthritis and sepsis, phospholipid metabolism shifts toward pro-inflammatory directions (e.g., excessive production of PGE₂); in chronic infections or tumors, accumulation of anti-inflammatory phospholipids (e.g., ceramide, PS) may lead to immune suppression, allowing pathogens or tumor cells to escape surveillance.

Phospholipids form a "molecular rheostat" for immune responses through their dual "pro-inflammatory-anti-inflammatory" regulation: in the early stages of infection, their pro-inflammatory effects initiate immune defense; during tissue repair, anti-inflammatory effects limit excessive inflammation to maintain tissue homeostasis. The regulatory mechanisms of this balance provide targets for disease treatment—for example, inhibiting PLA₂ or COX to reduce pro-inflammatory phospholipid metabolites can alleviate autoimmune diseases; supplementing anti-inflammatory phospholipids (e.g., EETs-containing liposomes) may be used to reduce acute inflammatory damage. In-depth analysis of dynamic changes in phospholipid metabolic networks will provide new ideas for precise intervention in immune-related diseases.