Loss of Protein Kinase D2 Activity Protects Against Bleomycin-Induced Dermal Fibrosis in Mice.
Loss of Protein Kinase D2 Activity Protects Against Bleomycin-Induced Dermal Fibrosis in Mice.
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蛋白激酶D2活性的丧失对博莱霉素诱导的小鼠皮肤纤维化具有保护作用。
DOI：
10.1016/j.labinv.2022.100018
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发表时间：
2023-02
影响因子：
5
通讯作者：
Wang, Q. Jane
中科院分区：
文献类型：
--
作者：
Chen, Liping;Zhao, Jinjun;Chao, Yapeng;Roy, Adhiraj;Guo, Wenjing;Qian, Jiabi;Xu, Wanfu;Domsic, Robyn T.;Lafyatis, Robert;Lu, Binfeng;Deng, Fan;Wang, Q. Jane
蛋白激酶 D (PKD) 与多种病理条件下的炎症反应有关；然而，其在炎症引起的真皮纤维化中的作用尚未得到评估。在本研究中，我们旨在研究蛋白激酶D2（PKD2）在炎症诱导的真皮纤维化中的作用和机制，并评估PKD抑制剂在该疾病中的治疗潜力。使用纯合激酶死亡 PKD2 敲入 (KI) 小鼠，我们在博莱霉素 (BLM) 诱导的皮肤纤维化模型中检查了 PKD2 活性的基因消融或药物抑制是否影响真皮炎症和纤维化。我们的数据显示，与野生型小鼠相比，BLM 处理的 PKD2 KI 小鼠的真皮厚度和胶原纤维显着减少，KI 小鼠中 α-平滑肌肌动蛋白和胶原蛋白的表达以及转化生长因子-β1 和白介素-6 的 mRNA 水平也显着减少。证实，CRT0066101 对 PKD 的药理抑制也显着阻断 BLM 诱导的真皮纤维化，并减少 α-平滑肌肌动蛋白、胶原蛋白和白细胞介素 6 的表达。进一步的分析表明，PKD2 活性的丧失显着阻止了 BLM 诱导的真皮中单核细胞/巨噬细胞和中性粒细胞的浸润。此外，使用骨髓来源的巨噬细胞，我们证明了 PKD 活性是细胞因子产生和巨噬细胞迁移所必需的。我们进一步确定 Akt 是纤维化过程早期炎症阶段 PKD2 的主要下游靶标。综上所述，我们的研究结果表明，PKD2 通过调节皮损皮肤中的免疫细胞浸润、细胞因子产生和下游 Akt 激活来促进真皮纤维化，而靶向抑制 PKD2 可能有利于这种情况的治疗。
Protein kinase D (PKD) has been linked to inflammatory responses in various pathologic conditions; however, its role in inflammation-induced dermal fibrosis has not been evaluated. In this study, we aimed to investigate the roles and mechanisms of protein kinase D2 (PKD2) in inflammation-induced dermal fibrosis and evaluate the therapeutic potential of PKD inhibitors in this disease. Using homozygous kinase-dead PKD2 knock-in (KI) mice, we examined whether genetic ablation or pharmacologic inhibition of PKD2 activity affected dermal inflammation and fibrosis in a bleomycin (BLM)-induced skin fibrosis model. Our data showed that dermal thickness and collagen fibers were significantly reduced in BLM-treated PKD2 KI mice compared with that in wild-type mice, and so was the expression of α-smooth muscle actin and collagens and the mRNA levels of transforming growth factor-β1 and interleukin-6 in the KI mice. Corroboratively, pharmacologic inhibition of PKD by CRT0066101 also significantly blocked BLM-induced dermal fibrosis and reduced α-smooth muscle actin, collagen, and interleukin-6 expression. Further analyses indicated that loss of PKD2 activity significantly blocked BLM-induced infiltration of monocytes/macrophages and neutrophils in the dermis. Moreover, using bone marrow–derived macrophages, we demonstrated that PKD activity was required for cytokine production and migration of macrophages. We have further identified Akt as a major downstream target of PKD2 in the early inflammatory phase of the fibrotic process. Taken together, our findings indicate that PKD2 promotes dermal fibrosis via regulating immune cell infiltration, cytokine production, and downstream activation of Akt in lesional skin, and targeted inhibition of PKD2 may benefit the treatment of this condition.
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丹酚酸 B 通过抑制 TGF-β 信号通路减轻实验性肺纤维化
影响因子：
4.6
作者：
Liu Q;Chu H;Ma Y;Wu T;Qian F;Ren X;Tu W;Zhou X;Jin L;Wu W;Wang J
通讯作者：
Wang J
影响因子：
27.4
作者：
Bergmann, Christina;Brandt, Amelie;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
5.7
作者：
LaValle CR;Zhang L;Xu S;Eiseman JL;Wang QJ
通讯作者：
Wang QJ
影响因子：
5
作者：
Smith, Gideon P;Chan, Edwin S L
通讯作者：
Chan, Edwin S L
DOI：
10.1042/bj20101188
发表时间：
2010-11-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Matthews SA;Navarro MN;Sinclair LV;Emslie E;Feijoo-Carnero C;Cantrell DA
通讯作者：
Cantrell DA