PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

Nakahigashi, Kyoko; Doi, Hiromi; Otsuka, Atsushi; Hirabayashi, Tetsuya; Murakami, Makoto; Urade, Yoshihiro; Tanizaki, Hideaki; Egawa, Gyohei; Miyachi, Yoshiki; Kabashima, Kenji

doi:10.1016/j.jaci.2011.11.034

Cited by 53 publications

(52 citation statements)

References 37 publications

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“…Indeed, in EPF lesions, our group and others detected H-PGDS-expressing cells in inflammatory infiltrates as cellular sources of PGD 2 . 30,38 The present study also found that hair follicle epithelium stained positive by immunohistochemistry for L-PGDS, another enzyme synthesizing PGD 2 , which may account for hair follicle accumulation of eosinophils. Interestingly, dermal eccrine glands/ducts, eccrine ostia in stratum corneum and epidermal keratinocytes around eosinophilic pustules were also positive for L-PGDS.…”

Section: Discussionsupporting

confidence: 73%

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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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Section: Discussionsupporting

confidence: 73%

“…37,38 Eotaxin synthesis, in principle, is stimulated by interleukin-4 and interleukin-13, which are 30,38 Prostaglandin D 2 and eotaxin may therefore co-exist in the lesional skin. We next assessed the effects of indomethacin on chemotaxis to PGD 2 in combination with eotaxin.…”

Section: And Eotaxin (Ccl11)mentioning

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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“…This directly suggests an important role for COX-2 signaling pathway in sebocyte biology as expression and activation of COX-2 has been shown in in vitro models to be PPARγ-mediated as well. It has been reported that additional lipid oxidizing agents that activate PPARγ could further induce lipogenesis in sebocytes (Nakahigashi et al 2012;Ruge et al 2011;Niemann and Horsley 2012). All these findings together allow the hypothesis that sebocyte differentiation and lipogenesis could be regulated by PPARγ-mediated pathways.…”

Section: Importance Of Sebaceous Lipids and Animal Modelsmentioning

confidence: 60%

“…Besides the lipid processing enzymes, we also have evidence that the most important lipid transcriptional factor, the peroxisome proliferating activated receptor gamma (PPARγ) is also required for the formation of sebaceous glands (Fu et al 2010), but in addition regulates sebocyte functions such as cellular responses to oxidative stress (Zhang et al 2006) and eotaxin production (Nakahigashi et al 2012).…”

Section: Importance Of Sebaceous Lipids and Animal Modelsmentioning

confidence: 99%

Sebaceous Lipids

Pappas¹

2014

Lipids and Skin Health

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Skin is protected by a layer of lipids, of both sebaceous and keratinocyte origin, which cover the surface of the skin. Different compositions of surface lipids have been reported depending on the method of sampling. Lipids produced by the epidermal cells are usually less per area in regions rich in sebaceous glands. The holocrine nature of the sebaceous gland will eventually result that the sebum will eventually coat the surface of the skin and the fur. The sebaceous lipids are primarily nonpolar lipids as triglycerides, wax esters, and squalene, while the epidermal lipids consist of ceramides, free-fatty acids, and cholesterol in almost equimolar concentrations. The composition of the sebaceous lipids manifests uniqueness and an intriguing biology exclusive to this gland. Elevated sebum excretion is a major factor involved in the pathophysiology of acne, therefore, an attempt to decode Core Messages• Human sebum is a mixture of nonpolar lipids: triglycerides, wax esters, squalene, fatty acids, and small amounts of cholesterol, cholesterol esters, and diglycerides.• Elevated sebum excretion is a major factor involved in the pathophysiology of acne and seboreeic dermatitis.• The sebaceous gland produces lipid species that are exclusive to sebumand cannot be found in other areas of the body.• Complexity and uniqueness characterize sebaceous lipids, since Δ6 monounsaturated chains, wax esters, and squalene accumulation are examples that manifest the uniqueness of sebaceous lipid biology.• Genetic knockout animal models of sebaceous lipid synthesis demonstrate dramatic changes in skin physiology and pathology. Impairment of sebaceous lipid pathways results to severe skin phenotypes. 128A. Pappas and elucidate the roles that these unique lipids have on normal skin functions and acne is imperative. Abbreviations KO Knock out SCStratum corneum VLCFA Very-long-chain fatty acids

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“…In fact, a recent study revealed that prostaglandin D2 stimulates sebocytes to produce eotaxin-3, a chemoattractant for eosinophils, thus supporting the clinical hypothesis that indomethacin is effective for EPF [11]. Although the pathogenetic aspects of EPF have been examined, there have been no epidemiological studies on patient characteristics, the types of medications used and their effectiveness.…”

Section: Discussionmentioning

confidence: 99%

Clinical Epidemiology of Eosinophilic Pustular Folliculitis: Results from a Nationwide Survey in Japan

Yamamoto

Nomura²,

Kabashima³

2014

Dermatology

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Background: No epidemiological study has examined the clinical characteristics, including medication use, of patients with eosinophilic pustular folliculitis (EPF). Objective: To describe the clinical characteristics for EPF and to examine the factors associated with the effectiveness of oral indomethacin for EPF. Methods: A cross-sectional study was performed of patients with EPF who visited the dermatology departments of the 67 main teaching facilities in Japan. We documented the patient characteristics and examined factors associated with the effectiveness of oral indomethacin. Results: A total of 145 patients with EPF were enrolled; 62.8% were prescribed oral indomethacin. A multivariable analysis revealed that female patients were more likely to exhibit complete response to oral indomethacin after adjustment for confounders (adjusted proportion ratio = 1.93, p = 0.04). Conclusion: Oral indomethacin has been accepted as a first-line treatment in EPF. Our results suggest that there is a sex difference in the treatment response to oral indomethacin.

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PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

Cited by 53 publications

References 37 publications

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

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

Sebaceous Lipids

Clinical Epidemiology of Eosinophilic Pustular Folliculitis: Results from a Nationwide Survey in Japan

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PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

Cited by 53 publications

References 37 publications

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

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

Sebaceous Lipids

Clinical Epidemiology of Eosinophilic Pustular Folliculitis: Results from a Nationwide Survey in Japan

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Product

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

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