Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C-C Motif Chemokine Ligand 20.
Keratin 17 Promotes T Cell Response in Allergic Contact Dermatitis by Upregulating C-C Motif Chemokine Ligand 20.
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角蛋白 17 通过上调 C−C 基序趋化因子配体 20 促进过敏性接触性皮炎中的 T 细胞反应
DOI：
10.3389/fimmu.2022.764793
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发表时间：
2022
影响因子：
7.3
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Luo Y;Zhu Z;Li B;Bai X;Fang H;Qiao P;Chen J;Zhang C;Zhi D;Dang E;Wang G
过敏性接触性皮炎(ACD)是一种对皮肤接触性变应原的迟发性超敏反应，角质形成细胞在早期反应的启动中起关键作用。角蛋白17(K17)是一种在应激条件下可诱导的细胞骨架蛋白，调节多种细胞过程，特别是在皮肤炎症性疾病中；然而，关于其在ACD发病机制中的作用尚不清楚。在本研究中，我们阐明了K17在恶唑酮(OXA)诱导的接触性超敏(CHS)小鼠模型中的促炎作用，并确定了其潜在的分子机制。我们的结果表明，K17在ACD患者和OXA诱导的CHS小鼠的皮肤中高度表达。缺乏K17的小鼠表现出减轻了OXA引起的皮肤炎症，包括较轻的耳朵肿胀，T细胞浸润频率减少，以及炎性细胞因子水平降低。在体外，K17刺激和激活角质形成细胞产生大量的促炎介质，特别是趋化因子CCL20，并促进角质形成细胞介导的T细胞转运。CCL20与CCL20中和单抗的中和显著减轻了OXA在体内引起的皮肤炎症。此外，K17可以通过依赖于核定位信号(NLS)和核输出信号(NES)序列的过程进入激活的角质形成细胞的核内，从而促进信号转导和转录激活因子3(STAT3)的激活和核转位，进而促进CCL20的产生和T细胞向皮损的转运。综上所述，这些结果强调了K17在驱动变应原诱导的皮肤炎症中的新作用，并建议将K17作为治疗ACD的潜在策略。
Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity response to skin contact allergens in which keratinocytes are critical in the initiation of early responses. Keratin 17 (K17) is a cytoskeletal protein inducible under stressful conditions and regulates multiple cellular processes, especially in skin inflammatory diseases; however, knowledge regarding its contribution to ACD pathogenesis remains ill defined. In the present study, we clarified the proinflammatory role of K17 in an oxazolone (OXA)-induced contact hypersensitivity (CHS) murine model and identified the underlying molecular mechanisms. Our results showed that K17 was highly expressed in the lesional skin of ACD patients and OXA-induced CHS mice. Mice lacking K17 exhibited alleviated OXA-induced skin inflammation, including milder ear swelling, a reduced frequency of T cell infiltration, and decreased inflammatory cytokine levels. In vitro, K17 stimulated and activated human keratinocytes to produce plenty of proinflammatory mediators, especially the chemokine CCL20, and promoted keratinocyte-mediated T cell trafficking. The neutralization of CCL20 with a CCL20-neutralizing monoclonal antibody significantly alleviated OXA-induced skin inflammation in vivo. Moreover, K17 could translocate into the nucleus of activated keratinocytes through a process dependent on the nuclear-localization signal (NLS) and nuclear-export signal (NES) sequences, thus facilitating the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), further promoting the production of CCL20 and T cell trafficking to the lesional skin. Taken together, these results highlight the novel roles of K17 in driving allergen-induced skin inflammation and suggest targeting K17 as a potential strategy for ACD.
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影响因子：
6.5
作者：
Kennedy-Crispin, Milene;Billick, Erika;Mitsui, Hiroshi;Gulati, Nicholas;Fujita, Hideki;Gilleaudeau, Patricia;Sullivan-Whalen, Mary;Johnson-Huang, Leanne M.;Suarez-Farinas, Mayte;Krueger, James G.
通讯作者：
Krueger, James G.
影响因子：
7.5
作者：
Babu, Sruthi;Mockler, Daniel C.;Shroyer, Kenneth R.
通讯作者：
Shroyer, Kenneth R.
影响因子：
10.7
作者：
Ehrlich, Florian;Lachner, Julia;Eckhart, Leopold
通讯作者：
Eckhart, Leopold
DOI：
10.1073/pnas.1704958114
发表时间：
2017-11-21
影响因子：
11.1
作者：
Getschman, A. E.;Imai, Y.;Volkman, B. F.
通讯作者：
Volkman, B. F.
DOI：
10.1016/j.ymthe.2017.10.005
发表时间：
2018-01-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Fülle L;Steiner N;Funke M;Gondorf F;Pfeiffer F;Siegl J;Opitz FV;Haßel SK;Erazo AB;Schanz O;Stunden HJ;Blank M;Gröber C;Händler K;Beyer M;Weighardt H;Latz E;Schultze JL;Mayer G;Förster I
通讯作者：
Förster I