Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor
Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor
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DOI：
10.4049/jimmunol.177.4.2621
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Nakamura, Masataka
中科院分区：
文献类型：
--
作者：
Satoh, Takahiro;Moroi, Rie;Nakamura, Masataka
PGD(2)通过特异性受体参与变态反应性炎症反应，其受体命名为DP和CRTH2(Th2细胞上表达的趋化受体同源分子)。我们产生了携带CRTH2基因靶向干扰的突变小鼠，以研究CRTH2在皮肤炎反应中的功能作用。CRTH2基因缺陷的小鼠可以生育，生长正常。半抗原特异性IgE诱导的耳肿胀反应在突变小鼠中不那么明显，给出了正常小鼠的35-55%的反应。在用造血PGD合成酶抑制剂HQL-79或CRTH2拮抗剂雷马特班治疗的小鼠中也看到了类似的结果。皮肤反应的减少与淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞的渗透减少以及炎症部位巨噬细胞衍生的趋化因子和RANTES的产生减少有关。在反复应用半抗原诱导的慢性接触过敏模型中，CRTH2缺乏导致大约一半的皮肤反应和低水平(对照的63%)血清IgE产生，尽管在体内CRTH2缺陷小鼠的朗格汉斯细胞和树突状细胞向区域淋巴结的迁移没有受到影响。相比之下，突变小鼠对SRBC的迟发性超敏反应和刺激性皮炎与野生型小鼠相同。这些发现表明，PGD(2)-CRTH2系统在慢性过敏性皮肤炎症中起重要作用。CRTH2可能是治疗包括特应性皮炎在内的人类过敏性疾病的一个新的治疗靶点。
PGD(2) plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35-55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD(2)-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.