COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity.

BACKGROUND

Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene [LT] C, prostaglandin [PG] D, and thromboxane A), which mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to nonclassical MC activation mechanisms.

OBJECTIVES

We sought to determine the regulation and significance of MC-derived eicosanoids synthesized in response to IL-33, a cytokine critical to innate type 2 immunity.

METHODS

We used an ex vivo model of mouse bone marrow-derived mast cells and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease (AERD).

RESULTS

IL-33 potently liberates AA and elicits LTC, PGD, and thromboxane A production by bone marrow-derived mast cells. Unexpectedly, the constitutive function of COX-1 is required for IL-33 to activate group IVa cytosolic phospholipase A with consequent AA release for synthesis of all eicosanoids, including CysLTs. In contrast, COX-1 was dispensable for FcεRI-driven CysLT production. Inhibition of COX-1 prevented IL-33-induced phosphorylation of extracellular signal-related kinase, an upstream effector of cytosolic phospholipase A, which was restored by exogenous PGH, implying that the effects of COX-1 required its catalytic function. Administration of a COX-1-selective antagonist to mice completely prevented the generation of both PGD and LTC in a model of AERD in which MC activation is IL-33 driven.

CONCLUSIONS

MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity and might help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in patients with AERD.