Can low EPA and arachidonic acid dominance reinforce chronic inflammation?

Resolving acute inflammation is an active, biochemically programmed process rather than a passive decay of inflammatory signals. When this program fails, a self-perpetuating molecular loop often drives chronic, non-resolving tissue inflammation.

Enzymatic Competition and Substrate Deprivation

At the cellular membrane level, eicosapentaenoic acid (EPA) and arachidonic acid (AA) compete directly for cyclooxygenase (COX-2) and lipoxygenase (5-LOX) enzymes.

• Substrate Starvation: When EPA availability is low, AA gains enzymatic priority, skewing metabolic flux toward highly potent, pro-inflammatory eicosanoids such as prostaglandin $\text{E}_2$ ($\text{PGE}_2$) and leukotriene $\text{B}_4$ ($\text{LTB}_4$).
• Impaired Resolution: This substrate imbalance deprives the tissue of 18-HEPE, the essential precursor required to synthesize E-series resolvins (like RvE1), directly limiting the pool of specialized pro-resolving mediators (SPMs).

The Self-Sustaining Inflammatory Loop

Physiologically, early-phase eicosanoids like $\text{PGE}_2$ and $\text{PGD}_2$ are programmed to trigger "lipid mediator class switching" by upregulating 15-LOX, instructing leukocytes to transition to SPM biosynthesis. Under conditions of AA dominance and low EPA, this transition is blocked:

• Persistent Innate Activation: Constant $\text{PGE}_2$ and $\text{LTB}_4$ signaling continually recruits and activates neutrophils and monocytes.
• Receptor Downregulation: The resulting chronic innate immune activation, marked by elevated TNF-α and IL-6, downregulates and mislocalizes critical SPM G-protein coupled receptors, including ALX/FPR2, ChemR23, and GPR32.
• Failure of Macrophage Polarization: Without active SPM-GPCR signaling, the microenvironment cannot promote M1-to-M2 macrophage polarization, leaving the innate immune system locked in a pro-inflammatory state.

Bottom line

• Low EPA availability and AA dominance establish a self-perpetuating cycle where substrate deprivation and cytokine-mediated receptor downregulation halt lipid mediator class switching, preventing M2 macrophage polarization and locking the innate immune system in a chronic inflammatory state.