Cyclooxygenase 1 mediates IL-33-induced extracellular signal regulated kinase activation in mast cells; Implications for aspirin sensitivity

Publication date: Available online 12 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Dingxin Pan, Kathleen M. Buchheit, Sachin K. Samuchiwal, Tao Liu, Haley Cirka, Hannah Raff, Joshua A. Boyce

Abstract

Background

Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene (LT)C₄, prostaglandin D₂ (PGD₂), and thromboxane A₂ (TXA₂)), that mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to non-classical MC activation mechanisms.

Objectives

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

Methods

We employed an ex vivo model of mouse bone marrow-derived MCs (BMMCs) and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease.

Results

IL-33 potently liberates AA and elicits LTC₄, PGD₂, and TXA₂ production by BMMCs. Unexpectedly, the constitutive function of cyclooxygenase (COX)-1 is required for IL-33 to activate group IVA cytosolic phospholipase A₂ (cPLA₂) 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 (ERK), an upstream effector of cPLA₂, which was restored by exogenous PGH₂, implying that the effects of COX-1 required its catalytic function. The administration of a COX-1-selective antagonist to mice completely prevented the generations of both PGD₂ and LTC₄ 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 may help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in AERD.

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