Skp2: A new therapeutic target of psoriasis.
Skp2: A new therapeutic target of psoriasis.
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Skp2：银屑病的新治疗靶点。
DOI：
10.1093/bjd/ljad479
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Arbiser,JackL
中科院分区：
文献类型：
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作者：
Wang,Ying;Arbiser,JackL
血管生成-从现有血管形成新血管的过程-在银屑病的发病机制中起着关键作用。1针对血管内皮生长因子（VEGF）的治疗，一种发育和病理性血管生成所必需的细胞因子，在银屑病的临床前研究中显示出有希望的效果。2然而，VEGF的全身抑制与副作用相关，3并且局部递送的抗VEGF疗法的功效仍不清楚。因此，确定银屑病血管生成的特异性分子介导物有望开发更有针对性和更有效的治疗方法。在本期BJD中，Xie等揭示了S期激酶相关蛋白2（Skp 2）作为银屑病中VEGF信号传导的下游组分。4通过分析患者和小鼠模型中的银屑病病变，他们确定了皮肤乳头内皮细胞中Skp 2的特异性诱导。来自不同测定的结果支持Skp 2在VEGF诱导的血管生成中的关键作用。值得注意的是，与VEGF缺乏导致胚胎死亡不同，5只Skp 2基因敲除的小鼠是存活的和可育的，表明Skp 2是发育性血管生成的抑制剂。然而，在咪喹莫特诱导的小鼠银屑病模型中，Skp 2的全局和内皮细胞特异性敲除显著降低了血管生成。尽管不排除Skp 2在VEGF的生理作用中的潜在作用，但这些结果强烈支持其在银屑病相关的病理性血管生成中的重要参与。Skp 2作为E3泛素连接酶，催化底物蛋白泛素化并导致蛋白水解或活性调节。Xie等人强调了Skp 2在介导内皮细胞中磷酸酶和张力蛋白同源物（PTEN）的泛素化和降解中的作用。4 PTEN是一种蛋白磷酸酶，是磷脂酰肌醇-3-激酶（PI 3 K）/蛋白激酶B（Akt）途径的负调节剂。该通路不仅介导缺氧诱导的VEGF增加，而且作为VEGF的下游组分，刺激内皮细胞增殖、迁移、存活和血管通透性。6这项研究广泛地检查了Skp 2对银屑病小鼠模型中微血管扩张和Akt磷酸化水平的影响。进一步探索Skp 2参与银屑病相关微血管通透性增高的研究是有价值的。此外，Xie等人报道了Skp 2的遗传缺陷和药理学抑制均广泛降低了鼠银屑病模型中的银屑病面积和严重程度指数评分。Skp 2的药理学抑制剂的功效已在各种类型的癌症中得到广泛评估。虽然银屑病通常不被认为是癌症的直接原因，但最近的研究报告称银屑病患者患癌症的风险增加。8鉴于Skp 2在不同条件下的不同蛋白质底物，可能需要开发靶向特定Skp 2-底物结合界面的抑制剂。尽管如此，目前的研究强调了Skp 2在银屑病和癌症中的双重靶向作用。最后，Skp 2介导的Akt在血管生成中的作用需要进一步研究。Akt在非退化性血管畸形和血管瘤中升高，9这是一种以其退化潜力而闻名的疾病。考虑到Akt在内皮细胞活力中的重要作用，探索Skp 2是否受普萘洛尔在血管瘤消退中的调节是有意义的。10此外，研究Skp 2是否在非退化性血管畸形中上调至关重要，因为Skp 2...
Angiogenesis–the process of forming new blood vessels from existing ones–plays a critical role in the pathogenesis of psoriasis. 1 Therapies targeting vascular endothelial growth factor (VEGF), a cytokine essential for both developmental and pathological angiogenesis, have shown promising effects in preclinical studies of psoriasis. 2 However, systemic inhibition of VEGF is associated with side-effects, 3 and the efficacy of topically delivered anti-VEGF therapies remains unclear. Therefore, identifying the specific molecular mediator of angiogenesis in psoriasis holds promise for the development of more targeted and effective therapies. In this issue of BJD, Xie et al. revealed S-phase kinaseassociated protein 2 (Skp2) as a downstream component of VEGF signalling in psoriasis. 4 By analysing psoriatic lesions in patients and mouse models, they identified the specific induction of Skp2 in dermal papillae endothelial cells. Results from diverse assays support the crucial role of Skp2 in VEGF-induced angiogenesis. Notably, unlike VEGF deficiency causing embryonic lethality, 5 mice with genetic knockout of Skp2 were viable and fertile, suggesting that Skp2 is dispensable for developmental angiogenesis. However, global and endothelial cell-specific knockout of Skp2 significantly reduced angiogenesis in imiquimodinduced mouse psoriasis models. While not excluding the potential roles of Skp2 in the physiological actions of VEGF, these results strongly support its crucial involvement in psoriasis-associated pathological angiogenesis. Skp2 acts as an E3 ubiquitin ligase, catalysing substrate protein ubiquitination and leading to proteolysis or activity modulation. Xie et al. highlighted the roles of Skp2 in mediating the ubiquitination and degradation of phosphatase and tensin homolog (PTEN) in endothelial cells. 4 PTEN is a protein phosphatase and a negative regulator of the phosphatidylinositol-3-kinase (PI3 K)/protein kinase B (Akt) pathway. This pathway not only mediates the hypoxia-induced increase of VEGF, but also serves as a downstream component of VEGF, stimulating endothelial cell proliferation, migration, survival and vascular permeability. 6 This study extensively examined the impact of Skp2 on the microvascular expansion and Akt phosphorylation levels in the murine models of psoriasis. Further exploration of the involvement of Skp2 in psoriasis-related microvascular hyperpermeabilities–an underexplored area–would be valuable. Furthermore, Xie et al. reported that both genetic deficiency and pharmacological inhibition of Skp2 extensively reduced the Psoriasis Area and Severity Index scores in the murine psoriasis models. 4 The efficacy of pharmacological inhibitors of Skp2 has been extensively evaluated in various types of cancers. 7 While psoriasis is generally not considered a direct cause of cancer, recent studies have reported an increased cancer risk in patients with psoriasis. 8 Given Skp2’s diverse protein substrates in different conditions, developing inhibitors targeting the specific Skp2–substrate binding interface is likely to be needed. Nevertheless, the current study underscores the dual-targeting roles of Skp2 in both psoriasis and cancer.Finally, the roles of Skp2-mediated regulation of Akt in angiogenesis needs further investigation. Akt is elevated in nonregressing vascular malformations and haemangioma, 9 a condition known for its regression potential. Given the important roles of Akt in endothelial viability, exploring whether Skp2 is regulated by propranolol in haemangioma regression is of interest. 10 Additionally, it is crucial to investigate whether Skp2 is upregulated in nonregressing vascular malformations, as Skp2 …