DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Miriam Peinhaupt,Rudolf Schicho,Eva M Sturm,Gunther Marsche,Marc E Rothenberg,Ian Sabroe,Anna Theiler,David Roula,Miriam Sedej,Akos Heinemann

doi:10.1002/jlb.3ma1017-404r

Abstract

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases.

Highlights

Numerous factors drive the progression of allergic conditions, affecting either the immediate, early, or the late phase of the allergic response
Since the D-type prostanoid receptor 1 (DP1) agonist BW245c prolonged the survival of eosinophils, we aimed to identify the pro-survival signals that were induced by DP1 receptor activation and to assess whether this function of PGD2 included the activation of programmed cell death pathways
To further elucidate the pro-survival signaling of the DP1 receptor and test the hypothesis that DP1 signaling modulates eosinophil function on a transcriptional level, we studied the potential of DP1 and DP2 to induce activation of serum response element (SRE)

Summary

Introduction

Numerous factors drive the progression of allergic conditions, affecting either the immediate, early, or the late phase of the allergic response. In the pivotal step of the inflammatory cascade mast cells release mediators such as histamine, prostaglandin (PG) D2, leukotriene C4, TNF- , and many others,[1] which start off the allergic response in the first place, induce the recruitment of inflammatory cells into the tissue and stimulate the surrounding and infiltrating cells to drive the transition from early to late phase, resulting. Eosinophils are considered as crucial effector cells in chronic allergic inflammation since they are involved in increasing epithelial-to-mesenchymal transition,[2,3] thickening of airway walls, airway hyperresponsiveness, and angiogenesis.[4,5] eosinophils are of major therapeutic interest in allergic diseases

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