Increased expression of CRTH2 on eosinophils in allergic skin diseases

Yahara, H.; Satoh, Takahiro; Miyagishi, Chiyako; Yokozeki, Hiroo

doi:10.1111/j.1468-3083.2009.03267.x

Cited by 32 publications

(18 citation statements)

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“…Our prior study suggested that there was a possible involvement of the PGD2-CRTH2 interaction in these diseases. 45 Most notably, the skin lesions found in these diseases are histologically characterized by a marked basophil infiltration. 46 Thus, basophil-derived PGD2 may at least partly contribute to the pathogenesis of these inflammatory skin reactions.…”

Section: Discussionmentioning

confidence: 99%

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Ugajin

Satoh

Kanamori

et al. 2011

The American Journal of Pathology

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Prostaglandin (PG) D2 and PGE2 are arachidonic acid metabolites that are generated though an isomerization reaction catalyzed by PG synthases. PGs have been implicated in immunologic reactions in addition to a wide range of physiological functions. It has long been thought that basophils, in contrast to mast cells, do not synthesize PGs, although they do release leukotrienes and platelet-activating factor. Here, we show that basophils function as a source of PGD2 and PGE2. In vitrocultured basophils from mouse bone marrow produced both PGD2 and PGE2 in response to IgE ؉ antigen (Ag), but not to IgG ؉ Ag. Release of PGs was almost completely abrogated in cultured basophils from FcR␥-chain ؊/؊ mice, indicating the involvement of Fc RI. Basophils freshly isolated from bone marrow cells (primary basophils) were also capable of secreting PGD2 and PGE2. Although the amount of PGD2 released from primary basophils was lower than that from mast cells, the capability of primary basophils to generate PGE2 was more potent than that of mast cells. Transcripts and proteins for both hematopoietic-type PGD synthase and PGE synthase were detected in basophils. In addition, human basophils, like mouse basophils, also produced PGD2 through IgE-mediated stimulation. Thus, basophils could be an important source of PGD2/ PGE2 and may contribute to allergic inflammation and immune responses. Prostaglandins, such as PGD2 and PGE2, are cyclooxygenase (COX) metabolites of arachidonic acids. They have a wide range of biological activities, including relaxation and contraction of smooth muscles, and modulation of neuronal activity. 1 PGD2 is principally produced by activated mast cells and, to a lesser extent, by T helper cell 2 (Th2) cells and dendritic cells 2-4 and exerts its effect through D prostanoid 5 and chemoattractant receptor-homologous molecule receptors expressed onTh2 lymphocytes (CRTH2). 6 A number of recent studies have shown that PGD2 is involved in inflammatory reactions. Mast cell-derived PGD2 suppresses IL-12 production by dendritic cells that induce Th2 responses in vivo. 7 PGD2 both activates and induces chemotaxis of Th2 cells, eosinophils, and basophils. 6 A large amount of PGD2 is detected in broncho-alveolar lavage fluid during allergen-induced airway inflammation. 8 Transgenic mice overexpressing human PGD synthase showed exacerbation of ovalbumin (OVA)-induced lung inflammation associated with pronounced eosinophilia and increased Th2 cytokine production. 9 In our previous studies, mice deficient in the CRTH2 gene were characterized by alleviated IgE-mediated cutaneous responses, contact hypersensitivity reactions, 10 and cedar pollen dermatitis. 11 However, PGE2 is produced by a variety of cells, including fibroblasts and macrophages, and exerts its effects via prostaglandin E2 (EP)1, EP2, EP3, and EP4 receptors. 12 PGE2 acts on T cells to enhance production of Th2-type cytokines and to inhibit production of Th1 cytokines in vitro, 13 whereas another study showed that PGE2 facilitates Th1 differentiation via EP...

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Section: Discussionmentioning

confidence: 99%

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

Ugajin

Satoh

Kanamori

et al. 2011

The American Journal of Pathology

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“…23 Expression of CRTH2 in eosinophils is increased in patients with atopic dermatitis, chronic urticaria or prurigo. 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.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

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

et al. 2013

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SummaryIndomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D 2 (PGD 2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD 2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD 2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of D 12 -PGJ 2 , a plasma metabolite of PGD 2 , on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD 2 -CRTH2 signals play major roles by reducing eosinophil responses to PGD 2 .

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“…29 CRTH2 expression is increased in eosinophils of atopic dermatitis, chronic urticaria, and in prurigo patients. 30 CRTH2-expressing T cells are elevated in the blood of atopic dermatitis. 31 Despite the different lines of evidence previously mentioned, the in vivo roles of DP in inflammation are somewhat controversial.…”

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confidence: 97%

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

Yamamoto

Otani

Hirai

et al. 2011

The American Journal of Pathology

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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.

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Increased expression of CRTH2 on eosinophils in allergic skin diseases

Abstract: The Student's t-test was used to assess the statistical significance of differences between mean values of healthy subjects and patients. *P < 0.05.Abbreviations: CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; PGD2 prostaglandin D2.

Cited by 32 publications

References 6 publications

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

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

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

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Increased expression of CRTH2 on eosinophils in allergic skin diseases

Abstract: The Student's t-test was used to assess the statistical significance of differences between mean values of healthy subjects and patients. *P < 0.05.Abbreviations: CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; PGD2 prostaglandin D2.

Cited by 32 publications

References 6 publications

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

FcεRI, but Not FcγR, Signals Induce Prostaglandin D2 and E2 Production from Basophils

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

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

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