Identification of polo-like kinase 1 as a therapeutic target in murine lupus.
Identification of polo-like kinase 1 as a therapeutic target in murine lupus.
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DOI：
10.1002/cti2.1362
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发表时间：
2022
影响因子：
5.8
通讯作者：
Wu T
中科院分区：
文献类型：
--
作者：
Li Y;Wang H;Zhang Z;Tang C;Zhou X;Mohan C;Wu T
导致狼疮发病机制的信号级联反应还不完全清楚。我们通过使用无偏的基于活性的小鼠狼疮激酶组筛选来解决这个问题。将196种激酶的无偏基于活性的激酶组筛选（ABKS）应用于两种遗传上不同的鼠狼疮株。在体内PLK 1阻断后评价系统性和肾性狼疮。还询问了PLK 1的上游调节子和下游靶标。注意到多个信号级联反应在鼠狼疮脾中更活跃，包括PLK 1。PLK 1特异性抑制剂的体内给药改善了MRL.lpr小鼠的脾肿大、抗dsDNA抗体产生、蛋白尿、BUN和肾脏病理学（P < 0.05）。PLK 1抑制后，血清IL-6、IL-17和肾损伤分子1（KIM-1）显著降低。PLK 1抑制减少了脾脏中的生发中心和边缘区B细胞，但T细胞的变化不显著。在体外，用抗小鼠CD 40 Ab或F（ab '）2片段抗小鼠IgM处理脾细胞。刺激24小时后，PLK 1阻断后IL-6分泌显著减少，而IL-10产生显著增加。在脾细胞亚群中评估mTOR的磷酸化，其揭示了髓样细胞中的显著变化。PLK 1阻断减少了与mTOR信号传导相关的磷酸化，而Aurora‐A成为PLK 1的潜在上游调节因子。Aurora‐A → PLK 1 → mTOR信号轴可能是狼疮发病机制的中心，并成为潜在的治疗靶点。在这项研究中，我们发现多个信号级联在小鼠狼疮脾脏中升高，包括PLK 1。在体内PLK 1阻断后，系统性和肾脏狼疮减轻。Aurora‐A → PLK 1 → mTOR信号轴可能是狼疮发病机制的中心，并成为潜在的治疗靶点。
The signalling cascades that contribute to lupus pathogenesis are incompletely understood. We address this by using an unbiased activity‐based kinome screen of murine lupus. An unbiased activity‐based kinome screen (ABKS) of 196 kinases was applied to two genetically different murine lupus strains. Systemic and renal lupus were evaluated following in vivo PLK1blockade. The upstream regulators and downstream targets of PLK1 were also interrogated. Multiple signalling cascades were noted to be more active in murine lupus spleens, including PLK1. In vivo administration of a PLK1‐specific inhibitor ameliorated splenomegaly, anti‐dsDNA antibody production, proteinuria, BUN and renal pathology in MRL.lpr mice (P < 0.05). Serum IL‐6, IL‐17 and kidney injury molecule 1 (KIM‐1) were significantly decreased after PLK1 inhibition. PLK1 inhibition reduced germinal centre and marginal zone B cells in the spleen, but changes in T cells were not significant. In vitro, splenocytes were treated with anti‐mouse CD40 Ab or F(ab’)2 fragment anti‐mouse IgM. After 24‐h stimulation, IL‐6 secretion was significantly reduced upon PLK1 blockade, whereas IL‐10 production was significantly increased. The phosphorylation of mTOR was assessed in splenocyte subsets, which revealed a significant change in myeloid cells. PLK1 blockade reduced phosphorylation associated with mTOR signalling, while Aurora‐A emerged as a potential upstream regulator of PLK1. The Aurora‐A → PLK1 → mTOR signalling axis may be central in lupus pathogenesis, and emerges as a potential therapeutic target. In this study, we found multiple signaling cascades were elevated in murine lupus spleens, including PLK1. Systemic and renal lupus were alleviated following in vivo PLK1 blockade. The Aurora‐A → PLK1 → mTOR signaling axis may be central in lupus pathogenesis and emerges as a potential therapeutic target.
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作者：
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