TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy.
TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy.
复制标题
DOI：
10.1126/sciimmunol.abi8823
复制
发表时间：
2021-11-19
影响因子：
24.8
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
Gupta RK;Gracias DT;Figueroa DS;Miki H;Miller J;Fung K;Ay F;Burkly L;Croft M
TNF和IL-17是两种驱动角化细胞活性失调的细胞因子，它们的靶向作用在银屑病患者中非常有效，但这些分子是否与其他炎症因子作用尚不清楚。在这里，我们发现角质形成细胞特异性缺失Fn14 （Tnfrsf12a）的小鼠，TNF超家族细胞因子TWEAK （Tnfsf12）的受体，表现出咪喹莫德诱导的皮肤炎症减少，包括表皮增生减少和牛皮癣特征基因的表达减少。这与Fn14在人牛皮癣病变的角质形成细胞中表达以及在几个皮肤细胞亚群中发现TWEAK相一致。人角质形成细胞的转录组学研究显示，TWEAK与IL-17A和TNF在上调CXC趋化因子表达方面存在强烈重叠，此外，IL-23等细胞因子、S100A8/9和SERPINB1/B9等炎症相关蛋白也在银屑病患者的病变皮肤中高度表达。重要的是，TWEAK与TNF或IL-17A在上调人角质形成细胞中许多银屑病相关基因mRNA方面表现出很强的协同作用，包括IL23A、IL36G和多种趋化因子，这意味着TWEAK与TNF和IL-17共同作用，增强反馈炎症活性。相应地，用抗TWEAK治疗小鼠在降低银屑病样皮肤炎症的临床和免疫学特征方面与IL-17A或TNF抗体同样有效，并且将TWEAK与任一细胞因子联合靶向治疗均没有更大的抑制作用，强化了这三种细胞因子共同起作用的结论。因此，阻断TWEAK可与靶向TNF或IL-17相媲美，可能被视为银屑病的替代治疗方法。TWEAK与角质形成细胞中的TNF和IL-17协同作用，驱动牛皮癣样皮肤炎症。
TNF and IL-17 are two cytokines that drive dysregulated keratinocyte activity and their targeting is highly efficacious in psoriasis patients, but whether these molecules act with other inflammatory factors is not clear. Here, we show that mice possessing a keratinocyte-specific deletion of Fn14 (Tnfrsf12a), the receptor for the TNF superfamily cytokine TWEAK (Tnfsf12), displayed reduced imiquimod-induced skin inflammation, including diminished epidermal hyperplasia and less expression of psoriasis signature genes. This corresponded with Fn14 being expressed in keratinocytes in human psoriasis lesions and TWEAK being found in several subsets of skin cells. Transcriptomic studies in human keratinocytes revealed that TWEAK strongly overlaps with IL-17A and TNF in upregulating the expression of CXC chemokines, along with cytokines such as IL-23, inflammation-associated proteins like S100A8/9 and SERPINB1/B9, all previously found to be highly expressed in the lesional skin of psoriasis patients. Importantly, TWEAK displayed strong synergism with TNF or IL-17A in upregulating mRNA for many psoriasis-associated genes in human keratinocytes, including IL23A, IL36G, and multiple chemokines, implying that TWEAK acts with TNF and IL-17 to enhance feedback inflammatory activity. Correspondingly, therapeutic treatment of mice with anti-TWEAK was equally as effective as antibodies to IL-17A or TNF in reducing clinical and immunological features of psoriasis-like skin inflammation, and combination targeting of TWEAK with either cytokine had no greater inhibitory effect, reinforcing the conclusion that all three cytokines function together. Thus, blocking TWEAK could be comparable to targeting TNF or IL-17 and might be considered as an alternate therapeutic treatment for psoriasis. TWEAK synergizes with TNF and IL-17 in keratinocytes to drive psoriasis-like skin inflammation.
登录
查看更多内容
影响因子：
7.3
作者：
Christmann C;Zenker S;Martens L;Hübner J;Loser K;Vogl T;Roth J
通讯作者：
Roth J
角质形成细胞中TNFα，IL-17A和EGF对IL-23的协同诱导。
影响因子：
3.8
作者：
Ehst B;Wang Z;Leitenberger J;McClanahan D;De La Torre R;Sawka E;Ortega-Loayza AG;Strunck J;Greiling T;Simpson E;Liu Y
通讯作者：
Liu Y
影响因子：
3.8
作者：
Bilgic, Ozlem;Sivrikaya, Abdullah;Altinyazar, Cevdet
通讯作者：
Altinyazar, Cevdet
DOI：
10.4049/jimmunol.1800013
发表时间：
2018-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hawkes JE;Yan BY;Chan TC;Krueger JG
通讯作者：
Krueger JG
DOI：
10.1016/j.jaci.2017.07.004
发表时间：
2017-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Hawkes JE;Chan TC;Krueger JG
通讯作者：
Krueger JG