Jiang Yanyun, Gruszka Dennis, Zeng Chang, Swindell William R, Gaskill Christa, Sorensen Christian, Brown Whitney, Gangwar Roopesh Singh, Tsoi Lam C, Webster Joshua, Sigurðardóttir Sigrún Laufey, Sarkar Mrinal K, Uppala Ranjitha, Kidder Austin, Xing Xianying, Plazyo Olesya, Xing Enze, Billi Allison C, Maverakis Emanual, Kahlenberg J Michelle, Gudjonsson Johann E, Ward Nicole L
Department of Dermatology, Ann Arbor, Michigan, USA.
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
JCI Insight. 2024 Mar 12;9(8):e172764. doi: 10.1172/jci.insight.172764.
IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator, also increased following TCF4 siRNA knockdown, and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together, these findings identify a role for TCF4 in the negative regulation of IL-17C, which, alone and with TNF-α and IL-17A, feed back to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation.
白细胞介素-17C（IL-17C）是一种上皮细胞源性促炎细胞因子，其转录调控尚不清楚。对IL17C启动子区域的分析确定转录因子4（TCF4）为假定调节因子，在人角质形成细胞（KC）中敲低TCF4的小干扰RNA（siRNA）可增加IL-17C。IL-17C对KC的刺激（连同IL-17A和肿瘤坏死因子-α刺激）以IL-17受体A/B（IL-17RA/RE）依赖的方式降低TCF4并增加NFKBIZ和锌指CCCH型含12A（ZC3H12A）的表达，从而形成一个反馈回路。转录免疫反应调节因子ZC3H12A（MCPIP1/去泛素化酶-1）在TCF4 siRNA敲低后也增加，敲低ZC3H12A的siRNA可降低NFKBIZ、白细胞介素-1β（IL-1B）、白细胞介素-36γ（IL36G）、趋化因子配体20（CCL20）和趋化因子CXC配体1（CXCL1），揭示了ZC3H12A的促炎作用。对KC-Tie2炎性皮肤病小鼠模型的皮损检查发现，TCF4蛋白减少，同时IL-17C和Zc3h12a增加，在基因敲除白细胞介素-17C（Il17c）、白细胞介素-17受体A（Il17ra）和白细胞介素-17受体B（Il17re）后这些变化逆转，皮肤表型得到改善。相反，在KC-Tie2小鼠皮肤中干扰Tcf4会增加Il17c并加剧炎性皮肤表型。总之，这些发现确定了TCF4在IL-17C负调控中的作用，IL-17C单独以及与肿瘤坏死因子-α和IL-17A一起以IL-17RA/RE依赖的方式反馈降低TCF4。IL-17C对ZC3H12A的自分泌调节以及IL-17C对NFKBIZ的调节进一步放大了这个回路，以促进皮肤炎症的自我维持。
