LCN2 Mediates Skin Inflammation in Psoriasis through the SREBP2-NLRC4 Axis
LCN2 Mediates Skin Inflammation in Psoriasis through the SREBP2-NLRC4 Axis
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LCN2 通过 SREBP2–NLRC4 轴介导银屑病皮肤炎症
DOI：
10.1016/j.jid.2022.01.012
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发表时间：
2022-07-20
影响因子：
6.5
通讯作者：
Shao, Shuai
中科院分区：
文献类型：
--
作者：
Ma, Jingyi;Chen, Jiaoling;Shao, Shuai
脂钙素是一类分泌脂肪因子，调节细胞脂质代谢和免疫反应。虽然我们之前已经发现LCN2调节银屑病中性粒细胞的激活，但LCN2在银屑病局部炎症中的其他作用仍然难以捉摸。在本研究中，我们发现LCN2的特异性受体24p3R在银屑病患者的病变表皮中高表达。在吡喹莫德诱导的银屑病样小鼠模型中，沉默24p3R（也称为slc22a17）可减轻角化过度、炎症细胞浸润和炎症介质的过度表达。在体外实验中，LCN2增强了原代角质形成细胞中IL-1b、IL-23、CXCL1和CXCL10等促炎因子的表达，这与强化的胆固醇生物合成信号传导是平行的。重要的是，通过体内和体外实验，我们发现胆固醇合成途径中的重要转录因子SREBP2是lcn2诱导角质形成细胞活化的关键介质，它与NLRC4的启动子区域结合。抑制小鼠SREBP2可减弱NLRC4信号和牛皮癣样皮炎。综上所述，本研究确定了LCN2-SREBP2-NLRC4轴在银屑病发病机制中的关键作用，并提出24p3R或SREBP2是银屑病的潜在治疗靶点。
Lipocalins are a family of secreted adipokines that regulate cell lipid metabolism and immune responses. Although we have previously revealed that LCN2 modulates neutrophil activation in psoriasis, the other roles of LCN2 in psoriatic local inflammation have remained elusive. In this study, we found that 24p3R, the well-known specific receptor of LCN2, was highly expressed in the lesional epidermis of patients with psoriasis. Silencing 24p3R (also known as slc22a17) alleviated hyperkeratosis, inflammatory cell infiltration, and overexpression of inflammatory mediators in an imiquimod-induced psoriasis-like mouse model. In vitro, LCN2 enhanced the expression of proinflammatory factors in primary keratinocytes, such as IL-1b, IL-23, CXCL1, and CXCL10, which was paralleled by enforced cholesterol biosynthetic signaling. Importantly, taking in vivo and in vitro approaches, we discovered the SREBP2, a vital transcriptional factor in cholesterol synthesis pathway, as the critical mediator of LCN2-induced keratinocyte activation, which bound to the promoter region of NLRC4. Suppressing SREBP2 in mice attenuated NLRC4 signaling and psoriasis-like dermatitis. Taken together, this study identifies the critical role of LCN2-SREBP2-NLRC4 axis in the pathogenesis of psoriasis and proposes 24p3R or SREBP2 as a potential therapeutic target for psoriasis.