致癌激酶 TOPK 在银屑病角质形成细胞中上调，并通过调节中性粒细胞浸润促进银屑病进展。
The oncogenic kinase TOPK upregulates in psoriatic keratinocytes and contributes to psoriasis progression by regulating neutrophils infiltration.
机构信息
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
出版信息
Cell Commun Signal. 2024 Aug 1;22(1):386. doi: 10.1186/s12964-024-01758-9.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.
背景
T-LAK 细胞定向蛋白激酶（TOPK）强烈促进癌细胞的恶性增殖，被认为是肿瘤进展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。尽管我们之前报道过局部抑制 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潜在机制仍不清楚。
方法
分析 GEO 数据集以研究 TOPK 与银屑病的关联。进行皮肤免疫组织化学（IHC）染色以阐明表达 TOPK 的主要细胞。使用 TOPK 条件性敲除（cko）小鼠研究 TOPK 特异性缺失在咪喹莫特诱导的银屑病样皮炎小鼠中的作用。使用流式细胞术分析病变皮肤中与银屑病相关的免疫细胞的变化。接下来，使用 M5 诱导的银屑病细胞模型通过 RNA-seq、RT-RCR 和 Western blot 鉴定潜在机制。最后，使用中性粒细胞中和抗体确认 TOPK 与小鼠银屑病样皮炎中性粒细胞之间的关系。
结果
我们发现 TOPK 水平与银屑病的进展密切相关。TOPK 在银屑病病变的表皮角质形成细胞中强烈增加，角质形成细胞中 TOPK 的条件性敲除抑制了中性粒细胞浸润并减轻了银屑病炎症。中性粒细胞通过中和抗体耗竭极大地减弱了 TOPK cko 在小鼠银屑病样皮炎中的抑制作用。此外，TOPK 抑制剂 OTS514 的局部应用可有效减轻小鼠已建立的银屑病样皮炎。机制上，RNA-seq 显示 TOPK 调节了白细胞介素 17 信号通路中某些基因的表达，如中性粒细胞趋化因子 CXCL1、CXCL2 和 CXCL8。TOPK 通过激活角质形成细胞中的转录因子 STAT3 和 NF-κB p65 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进展。
结论
本研究通过调节中性粒细胞浸润鉴定了 TOPK 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。
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