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

Abstract

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-1β, 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-γ 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-1β, 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.

Keywords: Aspirin; asthma; dupilumab; leukotriene; nonsteroidal anti-inflammatory drug; prostaglandin E(2).