Oka Tomonori, Sugaya Makoto, Takahashi Naomi, Takahashi Takehiro, Shibata Sayaka, Miyagaki Tomomitsu, Asano Yoshihide, Sato Shinichi
Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
J Immunol. 2017 May 15;198(10):3897-3908. doi: 10.4049/jimmunol.1601607. Epub 2017 Apr 7.
CXCL17 is expressed in a variety of cancers and promotes tumor progression by recruiting myeloid-derived suppressor cells (MDSCs). MDSCs suppress tumor immunity by attracting regulatory T cells (Tregs) into tumor sites through CCL5. In this study, we examined the role of CXCL17 in skin disorders. CXCL17 mRNA levels in psoriasis skin, but not in lesional skin of atopic dermatitis or cutaneous T cell lymphoma, were significantly higher than those in normal skin. CXCL17 was mainly expressed in the epidermis, and IFN-γ dose-dependently increased CXCL17 expression by human keratinocytes in vitro. As CXCL17 mRNA expression was increased by treatment with imiquimod (IMQ), we examined the effects of CXCL17 in IMQ-induced psoriasis-like skin inflammation. Injection of recombinant CXCL17 into the ear before and during IMQ application decreased ear thickness, inflammatory cytokine expression, and the number of infiltrating cells compared with PBS injection. Flow cytometric analysis and immunofluorescent staining revealed that the numbers of MDSCs, which are CD11bGr-1, and that of Tregs, which are CD4CD25, were higher in the ear of the CXCL17-injected mice than in PBS-injected mice. MDSCs, but not Tregs, showed chemotaxis to CXCL17 in vitro. When mice were injected with anti-CCL5 Ab or anti-CCL4 Ab simultaneously with recombinant CXCL17, ear thickness and cytokine expression increased to a similar level of mice treated with PBS and control IgG, suggesting that these chemokines were important for anti-inflammatory effects. Taken together, CXCL17 attenuates IMQ-induced psoriasis-like skin inflammation by recruiting MDSCs and Tregs, which may be important for regulating excessive inflammation in psoriasis skin.
CXCL17在多种癌症中表达，并通过招募髓源性抑制细胞（MDSCs）促进肿瘤进展。MDSCs通过CCL5将调节性T细胞（Tregs）吸引到肿瘤部位来抑制肿瘤免疫。在本研究中，我们研究了CXCL17在皮肤疾病中的作用。银屑病皮肤中CXCL17 mRNA水平显著高于正常皮肤，而特应性皮炎或皮肤T细胞淋巴瘤的皮损中则不然。CXCL17主要在表皮表达，体外γ干扰素（IFN-γ）可剂量依赖性增加人角质形成细胞CXCL17的表达。由于咪喹莫特（IMQ）处理可增加CXCL17 mRNA表达，我们研究了CXCL17在IMQ诱导的银屑病样皮肤炎症中的作用。与注射磷酸盐缓冲液（PBS）相比，在应用IMQ之前和期间向耳部注射重组CXCL17可降低耳部厚度、炎性细胞因子表达及浸润细胞数量。流式细胞术分析和免疫荧光染色显示，注射CXCL17的小鼠耳部中CD11bGr-1阳性的MDSCs数量及CD4CD25阳性的Tregs数量高于注射PBS的小鼠。体外实验中，MDSCs而非Tregs对CXCL17表现出趋化性。当小鼠同时注射抗CCL5抗体或抗CCL4抗体与重组CXCL17时，耳部厚度和细胞因子表达增加至与注射PBS和对照IgG的小鼠相似水平，提示这些趋化因子对抗炎作用很重要。综上所述，CXCL17通过招募MDSCs和Tregs减轻IMQ诱导的银屑病样皮肤炎症，这可能对调节银屑病皮肤中的过度炎症很重要。
