Mechanisms by which dupilumab normalizes eicosanoid metabolism and restores aspirin- tolerance in AERD: A hypothesis

Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase- dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-113, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-g induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-113, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance. (J Allergy Clin Immunol 2023;151:310-3.)

Automated summary

Aspirin-exacerbated respiratory disease (AERD) is characterized by excessive cysteinyl leukotrienes (CysLTs) production, reduced prostaglandin E2 (PGE2) synthesis and downregulated expression of the EP2 receptor. The dysregulation of the COX-2 pathway in AERD is attributed to alterations in the autocrine metabolic loop involving IL-113, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Blocking IL-4 with dupilumab can normalize the expression of EP2, restore the functioning of the COX-2 pathway, and improve aspirin tolerance.