The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-08-01 DOI:10.1186/s12964-024-01758-9

Fanfan Zeng, Shuaixian Du, Mengjun Wu, Chan Dai, Jianyu Li, Jinbiao Wang, Guoyun Hu, Pengcheng Cai, Lin Wang

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Abstract

T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.

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致癌激酶 TOPK 在银屑病角朊细胞中上调，并通过调节中性粒细胞的浸润促进银屑病的发展

T-LAK细胞导向蛋白激酶（TOPK）能强烈促进癌细胞的恶性增殖，被认为是肿瘤进展的一种有前途的生物标志物。银屑病是一种常见的炎症性皮肤病，其特征是角质形成细胞过度增殖。虽然我们以前曾报道过局部抑制 TOPK 可抑制银屑病样模型小鼠的银屑病表现，但 TOPK 在银屑病炎症中的确切作用及其内在机制仍未确定。为了研究 TOPK 与银屑病的关系，我们分析了 GEO 数据集。进行了皮肤免疫组化（IHC）染色，以明确表达 TOPK 的主要细胞。利用TOPK条件性基因敲除（cko）小鼠研究TOPK特异性缺失在IMQ诱导的小鼠银屑病样皮炎中的作用。流式细胞术用于分析病变皮肤中银屑病相关免疫细胞的变化。接着，通过RNA-seq、RT-RCR和Western blotting，使用M5诱导的银屑病细胞模型来确定潜在的机制。最后，利用中性粒细胞中和抗体证实了小鼠银屑病样皮炎中 TOPK 与中性粒细胞之间的关系。我们发现，TOPK 水平与银屑病的进展密切相关。TOPK主要在银屑病皮损的表皮角朊细胞中增加，条件性敲除角朊细胞中的TOPK可抑制中性粒细胞浸润，减轻银屑病炎症。通过中和抗体删除中性粒细胞大大削弱了 TOPK cko 对小鼠银屑病样皮炎的抑制作用。此外，局部应用 TOPK 抑制剂 OTS514 能有效减轻小鼠已形成的银屑病样皮炎。从机制上看，RNA-seq发现TOPK调节IL-17信号通路中一些基因的表达，如中性粒细胞趋化因子CXCL1、CXCL2和CXCL8。TOPK 通过激活角朊细胞中的转录因子 STAT3 和 NF-κB p65 来调节中性粒细胞趋化因子的表达，从而促进中性粒细胞浸润和银屑病的发展。这项研究发现了 TOPK 通过调节中性粒细胞浸润在银屑病中的关键作用，为银屑病的发病机制提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.

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