Increased Lipocalin-2 Contributes to the Pathogenesis of Psoriasis by Modulating Neutrophil Chemotaxis and Cytokine Secretion
Increased Lipocalin-2 Contributes to the Pathogenesis of Psoriasis by Modulating Neutrophil Chemotaxis and Cytokine Secretion
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Lipocalin-2 增加通过调节中性粒细胞趋化性和细胞因子分泌促进银屑病的发病机制
DOI：
10.1016/j.jid.2016.03.002
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发表时间：
2016-07-01
影响因子：
6.5
通讯作者：
Wang, Gang
中科院分区：
文献类型：
--
作者：
Shao, Shuai;Cao, Tianyu;Wang, Gang
牛皮癣的特点是对感染具有抵抗力，这是由抗菌蛋白调节的。抗菌蛋白是否在牛皮癣中起致病作用尚不清楚。在这项研究中，我们旨在阐明脂钙素-2(Lcn2)，一种抗菌蛋白，在银屑病发病机制中的作用。结果表明，Lcn2在银屑病患者皮损中高表达。在咪喹莫特诱导的银屑病样小鼠模型中，Lcn2的中和减轻了表皮增生、炎症，特别是中性粒细胞的渗透。在体外，Lcn2通过中性粒细胞上的特异性受体24p3R刺激中性粒细胞产生重要的促炎介质，如IL-6、IL-8、肿瘤坏死因子-α和IL-1α，从而激活下游的细胞外信号调节激酶-1/2和p38-丝裂原激活的蛋白激酶信号通路。此外，在体外，Lcn2诱导的中性粒细胞趋化作用具有浓度依赖性，并由细胞外信号调节激酶-1/2和p38-丝裂原活化蛋白激酶信号通路介导。此外，我们还证明角质形成细胞和中性粒细胞都是银屑病患者皮损中Lcn2的来源。综上所述，这些结果提示Lcn2可能通过调节中性粒细胞功能参与银屑病的发病过程，有可能成为治疗银屑病的潜在靶点。
Psoriasis is characterized by resistance to infections, which is regulated by antimicrobial proteins. Whether antimicrobial proteins play a pathogenic role in psoriasis remains unclear. In this study, we aimed to elucidate the role of lipocalin-2 (Lcn2), an antimicrobial protein, in the pathogenesis of psoriasis. Our results showed that Lcn2 was highly expressed in the lesional skin of psoriatic patients. The neutralization of Lcn2 alleviated epidermal hyperplasia, inflammation, and especially neutrophil infiltration in an imiquimod-induced psoriasis-like murine model. In vitro, Lcn2 stimulated human neutrophils to produce vital proinflammatory mediators, such as IL-6, IL-8, tumor necrosis factor-alpha, and IL-1 alpha via a specific receptor, 24p3R, on neutrophils, which consequently activated the downstream extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways. Moreover, Lcn2-induced neutrophil chemotaxis was concentration dependent and mediated by the extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways in vitro. Furthermore, we demonstrated that both keratinocytes and neutrophils were the sources of Lcn2 in the lesional skin of psoriatic patients. Taken together, these results suggest that Lcn2 is involved in the pathogenesis of psoriasis by modulating neutrophil function, and that it could serve as a potential target for treating psoriasis.