Therapeutic Potential of Hematopoietic Prostaglandin D2 Synthase in Allergic Inflammation

Abstract

Worldwide, there is a rise in the prevalence of allergic diseases, and novel efficient therapeutic approaches are still needed to alleviate disease burden. Prostaglandin D₂ (PGD₂) has emerged as a central inflammatory lipid mediator associated with increased migration, activation and survival of leukocytes in various allergy-associated disorders. In the periphery, the hematopoietic PGD synthase (hPGDS) acts downstream of the arachidonic acid/COX pathway catalysing the isomerisation of PGH₂ to PGD₂, which makes it an interesting target to treat allergic inflammation. Although much effort has been put into developing efficient hPGDS inhibitors, no compound has made it to the market yet, which indicates that more light needs to be shed on potential PGD₂ sources and targets to determine which particular condition and patient will benefit most and thereby improve therapeutic efficacy. In this review, we want to revisit current knowledge about hPGDS function, expression in allergy-associated cell types and their contribution to PGD₂ levels as well as beneficial effects of hPGDS inhibition in allergic asthma, rhinitis, atopic dermatitis, food allergy, gastrointestinal allergic disorders and anaphylaxis.

Keywords: DP receptors; PGD2; allergic inflammation; eosinophilic inflammation; hPGDS; hPGDS inhibitor.

Figure 1

hPGDS as therapeutic target downstream of the arachidonic acid/cyclooxygenase (COX) pathway. Hematopoietic PGDS inhibition specifically targets PGD₂ and PGD₂ metabolite production—mediators that primarily activate pro-inflammatory DP2/CRTH2 receptor [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) block all lipid mediators downstream of COX-1/2, including potentially beneficial effects of PGE₂ and PGI₂. Corticosteroids are standard-of-care therapeutics of asthmatic patients that effectively block all downstream products of arachidonic acid including leukotrienes; however, therapy interferes with many physiological processes causing numerous adverse effects. Favorable effects of selected lipid mediators in allergic inflammation highlighted in green; unfavorable effects highlighted in red.

Figure 2

Potential target cells and beneficial effects of hPGDS inhibition in allergic inflammation. Hematopoietic PGDS expression has been reported in many cell types involved in allergic inflammation. Elevated PGD₂ levels have been shown to induce DP2/CRTH2-mediated smooth muscle cell proliferation and hyperresponsiveness [103], macrophage activation [11], nasal blockage [10] as well as influx, activation and survival of eosinophils, ILC2s and Th2 cells. Inhibition of hPGDS-derived PGD₂ production would target all above-mentioned pathological phenomena.

Figure 3

Experimental overexpression, inhibition and knock-out of hPGDS differentially modulates acute and chronic inflammation. Overexpression of transgenic hPGDS in mice resulted in reduced ear swelling and vascular permeability in the acute phase of inflammation, however, it exacerbated leukocyte influx in the late phase; In the same model, hPGDS knock-out potentiated vascular extravasation during acute skin inflammation [12]. Neutrophil influx and lung damage was more prominent in hPGDS knock-out mice [14]. In contrast, hPGDS inhibition proved to be beneficial in experimental models of allergic inflammation [28,119,120]. Interestingly, hPGDS over-expression was able to reduce the number of intestinal tumors, while hPGDS knock-out showed the opposite effect [27].