Prostaglandin E2 in NSAID-exacerbated respiratory disease: protection against cysteinyl leukotrienes and group 2 innate lymphoid cells

Abstract

Purpose of review: The purpose of this review is to describe the recent advances that have been made in understanding the protective role of prostaglandin E2 (PGE2) in aspirin-exacerbated respiratory disease (AERD), known in Europe as NSAID-exacerbated respiratory disease (N-ERD).

Recent findings: Decreased PGE2 signaling through the EP2 receptor in patients with AERD leads to an increase in leukotriene synthesis and signaling. Leukotriene signaling not only directly activates group 2 innate lymphoid cells and mast cells, but it also increases production of IL-33 and thymic stromal lymphopoietin. These cytokines drive Th2 inflammation in a suspected feed-forward mechanism in patients with AERD.

Summary: Recent discoveries concerning the role of PGE2 in leukotriene synthesis and signaling in AERD, as well as downstream effects on group 2 innate lymphoid cells and mast cells, allow for a more comprehensive understanding of the pathogenesis of this disease. These discoveries also identify new paths of potential investigation and possible therapeutic targets for AERD.

Figure 1.

Known (left-section): The above figure describes the pathways of leukotriene and prostaglandin synthesis, and how these products affect inflammation and asthma. Pro-inflammatory signaling is represented with arrows, while protective, anti-inflammatory signaling is represented with perpendicular line-heads. The CysLTs LTC₄, LTD₄, and LTE₄ are expressed by neutrophil adhering platelets, mast cells, eosinophils, and basophils. CysLTs signal through the CysLT Receptors CysLT₁R, CysLT₂R, and CysLT₃R on T cells, macrophages, granulocytes, smooth-muscle cells and other cell types to propagate bronchoconstriction, mucin release, and inflammation (blue-dotted line). This encompasses the traditional understanding of CysLT-mediated asthma symptoms. PGE₂ (red-dotted line) protects against these symptoms by inhibiting 5-LO (responsible for CysLT synthesis) and signaling through the EP₂ receptor on T cells, macrophages, granulocytes, smooth-muscle cells and other pro-inflammatory cell types that are activated by CysLTs. Newly proposed mechanisms (right section): CysLTs cause increases in TSLP and IL-33 in the lung. TSLP and IL-33 are released from Type 2 alveolar cells and epithelial cells from cell stress, necrosis, or contact with aeroallergens. IL-33/TSLP act synergistically with CysLTs to activate group 2 innate lymphoid cells (ILC2) and mast cells. IL-33 signals through ST2, TSLP signals through TSLPR, and CysLTs signal through the CysLT receptors. This synergistic signaling causes ILC2 to release large quantities of IL-5 and IL-13. IL-13 then induces the increased expression of IL-33 in epithelial cells. CysLT and IL-33/TSLP signaling also causes mast cells to produce histamine, tryptase, PGD₂, and LTC₄. The LTC₄ released by mast cells (black-solid line) drives asthma as previously described, but LTC₄ also acts back upstream by increasing concentrations of IL-33 and TSLP in type 2 pneumocytes and likely epithelial cells. Increased quantities of IL-33 and TSLP drive a prolonged inflammatory response acting in synergy with CysLTs. PGE₂ inhibits ILC2 and mast cell activation, further suggesting PGE₂ dysregulation as a central cause of AERD.