The potential anti-inflammatory effect of phosphatidylserine

Phosphatidylserine (PS), a phospholipid molecule widely present in cell membranes, is associated with inflammatory responses not only through maintaining cellular structure but also by regulating inflammatory signaling pathways, immune cell functions, and oxidative stress balance, thereby exhibiting potential anti-inflammatory effects. The scientific basis for this role stems from its multi-level intervention in the inflammatory cascade.

I. Inhibiting Inflammatory Initiation by Regulating Membrane Homeostasis

The cell membrane serves as the frontline for perceiving external stimuli (including inflammatory signals), and the distribution and structural properties of phosphatidylserine directly influence the initial activation of inflammation:

Maintaining membrane integrity to reduce release of damage-associated molecular patterns (DAMPs): When cells are subjected to infection, trauma, or oxidative stress, membrane disruption releases DAMPs (e.g., ATP, histones), which activate inflammatory receptors (e.g., Toll-like receptor TLR4) on immune cells, triggering inflammatory responses. Phosphatidylserine forms stable lipid complexes with cholesterol and other phospholipids in the membrane, enhancing mechanical strength and damage resistance, thereby reducing abnormal DAMP release and lowering the "initiating source" of inflammatory signals.

Modulating expression and conformation of membrane-bound inflammatory receptors: Inflammatory receptors (e.g., TLR4, TNF-α receptors) on immune cells (e.g., macrophages, neutrophils) are key nodes for inflammatory signal transmission. Phosphatidylserine binds to these receptors via electrostatic or hydrophobic interactions, altering their spatial conformation and inhibiting ligand (e.g., LPS, TNF-α) binding efficiency, thus blocking transmembrane transmission of inflammatory signals at the source.

II. Regulating Inflammatory Signaling Pathways to Block the Inflammatory Cascade

Phosphatidylserine’s intervention in inflammatory signaling pathways is central to its anti-inflammatory effects, primarily through inhibiting pro-inflammatory signal transduction and enhancing anti-inflammatory signal expression:

Suppressing excessive activation of the NF-κB pathway: Nuclear factor κB (NF-κB) is a key transcription factor regulating the expression of pro-inflammatory genes (e.g., IL-1β, IL-6, TNF-α), acting as a "switch" in inflammatory responses. Studies show that phosphatidylserine inhibits the activity of IκB kinase (IKK), preventing phosphorylation and degradation of the inhibitory protein IκB. This maintains NF-κB in an "inactive state" in the cytoplasm, reducing synthesis and release of pro-inflammatory cytokines and blocking the amplification of inflammation.

Activating anti-inflammatory pathways such as Nrf2/HO-1: Phosphatidylserine activates nuclear factor E2-related factor 2 (Nrf2), promoting its translocation into the nucleus to bind antioxidant response elements (ARE), thereby upregulating the expression of anti-inflammatory proteins such as heme oxygenase-1 (HO-1). HO-1 catalyzes heme degradation into carbon monoxide (CO), bilirubin, and other anti-inflammatory substances, inhibiting pro-inflammatory polarization of macrophages (e.g., M1 polarization) while promoting differentiation into anti-inflammatory phenotypes (e.g., M2), regulating the balance between "pro-inflammatory and anti-inflammatory" responses.

III. Modulating Immune Cell Functions to Reduce Inflammatory Infiltration and Damage

Abnormal activation and excessive infiltration of immune cells are critical drivers of exacerbated inflammation. PS exerts anti-inflammatory effects by targeting immune cell functions:

Inhibiting neutrophil recruitment and activation: Neutrophils are the primary immune cells infiltrating early in inflammation, and their release of neutrophil elastase and reactive oxygen species (ROS) exacerbates tissue damage. Phosphatidylserine binds to integrins (e.g., Mac-1) on neutrophils, inhibiting adhesion to vascular endothelial cells and reducing migration to inflammatory sites. Additionally, PS reduces respiratory burst activity in neutrophils, decreasing ROS and cytokine release to mitigate tissue inflammatory damage.

Regulating macrophage phenotypic switching: The balance between M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages is a key regulatory point in inflammation. Phosphatidylserine inhibits the TLR4-mediated MyD88 signaling pathway in macrophages, reducing the expression of M1 markers (e.g., IL-1β, TNF-α) while promoting secretion of M2 markers (e.g., IL-10, TGF-β). This enhances the anti-inflammatory and tissue repair functions of macrophages, shifting inflammation from the "destructive phase" to the "repair phase."

IV. Indirectly Alleviating Inflammation by Inhibiting Oxidative Stress

Oxidative stress and inflammation often form a "vicious cycle"—ROS accumulation activates inflammatory signals, while inflammatory cells release more ROS. The antioxidant properties of phosphatidylserine (e.g., stabilizing mitochondrial membranes, enhancing glutathione system activity) reduce ROS production, thereby indirectly inhibiting oxidative stress-dependent inflammatory pathways:

Protecting mitochondrial function to reduce pro-inflammatory factor release: Mitochondria are major sources of ROS; dysfunction leads to excessive ROS accumulation and release of mitochondrial DNA (mtDNA, a DAMP), further activating inflammation. Phosphatidylserine stabilizes mitochondrial membrane potential and inhibits opening of the mitochondrial permeability transition pore, reducing mtDNA release and ROS generation, thus 切断 the positive feedback loop between oxidative stress and inflammation.

Reducing pro-inflammatory effects of lipid peroxidation products: Lipid peroxidation products (e.g., 4-hydroxynonenal) from oxidative stress activate inflammatory receptors, exacerbating inflammation. Phosphatidylserine inhibits membrane lipid peroxidation (e.g., stabilizing unsaturated fatty acid structures), reducing production of these pro-inflammatory intermediates and indirectly alleviating sustained stimulation of inflammatory signals.

V. Targeted Anti-Inflammatory Performance in Specific Tissues

The anti-inflammatory effects of phosphatidylserine are particularly prominent in tissues such as the nervous and cardiovascular systems:

Protective effects in neuroinflammation: Overactivation of microglia is a core feature of neuroinflammation (e.g., Alzheimer’s disease, traumatic brain injury). Phosphatidylserine crosses the blood-brain barrier, inhibits pro-inflammatory activation of microglia, reduces release of neurotoxic factors (e.g., IL-1β, NO), and protects neurons from inflammatory damage.

Regulatory roles in cardiovascular inflammation: Atherosclerosis is essentially chronic inflammation of the vascular wall. Phosphatidylserine inhibits expression of adhesion molecules (e.g., VCAM-1, ICAM-1) in vascular endothelial cells, reducing monocyte infiltration into the vascular intima and slowing the formation and progression of atherosclerotic plaques.

The potential anti-inflammatory effects of phosphatidylserine are achieved through multi-pathway synergy: "inhibiting inflammatory initiation, blocking signal transduction, regulating immune function, and improving oxidative stress." Its maintenance of membrane homeostasis, precise regulation of inflammatory signaling pathways, and directional modulation of immune cell phenotypes provide a scientific basis for its application in preventing and intervening in chronic inflammation-related diseases (e.g., neurodegenerative diseases, cardiovascular diseases) and offer potential targets for developing novel anti-inflammatory strategies.