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 pro-inflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE), and reduced expression of the EP2 receptor for PGE. Reduced PGE synthesis results from the down-regulation of inducible cyclooxygenase 2 (COX-2). Since PGE signalling via EP2 inhibits the 5-lipoxygenase(5-LO)/Leukotriene C4 synthase (LTC4S)-dependent pathway, the deficient levels of both PGE and EP2 likely contribute to the excessive baseline production of CysLTs in AERD compared with aspirin-tolerant asthma patients. The COX-2 pathway is regulated by an autocrine metabolic loop involving interleukin IL-1β, IL-1RI, EP2, COX-2, mPGE-1 and PGE. Previous studies reported that this metabolic loop is dysregulated in AERD patients. When the down-expressed EP2 receptor is normalized, the entire loop returns to its normal function. Co-treatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in AERD patients. Interleukin 4, which is produced in excess in AERD airways, likely contributes to altering the normal functioning of the IL-1β, IL-1RI, EP2, COX-2, mPGE-1 and PGE autocrine metabolic loop in these patients. 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, normalizing the synthesis of PGE and thereby restoring aspirin tolerance.