Dual Functions of Prostaglandin D2 in Murine Contact Hypersensitivity via DP and CRTH2

Abstract

Prostaglandin D2 (PGD2) exerts its effects through two distinct receptors: the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid (DP) receptor. Our previous study demonstrated that CRTH2 mediates contact hypersensitivity (CHS) in mice. However, the function of DP receptor remains to be fully established. In this study, we examine the pathophysiological roles of PGD2 using DP-deficient (DP ؊/؊ ) and CRTH2/DP-deficient (CRTH2 ؊/؊ / DP ؊/؊ ) mice to elucidate receptor-mediated PGD2 action in CHS. We observed profound exacerbation of CHS in DP ؊/؊ mice. CRTH2 ؊/؊ /DP ؊/؊ mice showed similar exacerbation, but to a lesser extent. These symptoms were accompanied by increased production of interferon-␥ and IL-17. The increase in IL-17 producing ␥␦ T cells was marked and presumably contributed to the enhanced CHS. DP deficiency promoted the in vivo migration of dendritic cells to regional lymph nodes. A DP agonist added to DCs in vitro was able to inhibit production of IL-12 and IL-1␤. Interestingly, production of IL-10 in dendritic cells was elevated via the DP pathway, but it was lowered by the CRTH2 pathway. Collectively, PGD2 signals through CRTH2 to mediate CHS inflammation, and conversely, DP signals to exert inhibitory effects on CHS. Thus, we report opposing functions for PGD2 that depend on receptor usage in allergic reactions.

Mast Cell–Derived Prostaglandin D2 Inhibits Colitis and Colitis-Associated Colon Cancer in Mice

“…Several groups reported its pro-inflammatory properties, where PGD 2 was shown to enhance the chemotactic activity of immune cells and to accumulate them in inflamed sites, causing the aggravation of OVA-induced asthma in mice or OVAinduced rhinitis in guinea pigs (9,10). In contrast, other groups reported that PGD 2 exerted anti-inflammatory properties, where it attenuated 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity and zymosan-induced peritonitis in mice (11,12). Our group also showed that PGD 2 inhibits vascular permeability and inflammation in acute lung inflammation and implanted tumor models (13,14).…”

Indomethacin inhibits eosinophil migration to prostaglandin D2: therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis

“…24 Antagonists of CRTH2 ameliorate skin inflammation in IgE-mediated chronic skin responses, contact hypersensitivity and cedar pollen dermatitis in accordance with reduced numbers of dermal eosinophils. 20,21,25 Recent studies have identified indomethacin as a potent agonist of CRTH2, 26 causing PGD 2 -like and eotaxin (CCL11) -like responses in eosinophils. 27 These findings are somewhat inconsistent, offering clinical evidence that indomethacin is a useful therapeutic tool for EPF 3,4 and other eosinophilic skin diseases, such as angiolymphoid hyperplasia with eosinophilia 28 and recurrent cutaneous eosinophilic vasculitis.…”

“…19 Prostaglandin D 2 promotes skin inflammation of IgE-mediated chronic skin responses and the elicitation phase of contact hypersensitivity. 20,21 Biological activities of PGD 2 are mediated by the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and the D prostanoid receptor. These receptors are members of the G protein-coupled, seven transmembrane receptor family.…”

Exacerbation of Aging‐Associated and Instability‐Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D2 Receptor

“…PGD 2 elicits its downstream effects by activating 2 plasma membrane receptors, D prostanoid receptor 1 (DP1) (8) and chemoattractant receptorlike molecule expressed on Th2 cells (CRTH2), also known as DP2 (9). Activation of DP1 receptors is primarily associated with antiinflammatory effects (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). PGD 2 has also been shown to modulate inflammation, acting as either a proinflammatory or antiinflammatory mediator, depending on the pathologic condition and the affected tissue.…”