<br>Cdc42 的髓系缺失通过抑制巨噬细胞介导的炎症来保护小鼠肝脏免受缺血再灌注损伤,Cellular and Molecular Gastroenterology and Hepatology

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Cdc42 的髓系缺失通过抑制巨噬细胞介导的炎症来保护小鼠肝脏免受缺血再灌注损伤
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2024-02-09 , DOI: 10.1016/j.jcmgh.2024.01.023
Jing He ₁ , Meng-Yu Tang ₂ , Li-Xin Liu ₃ , Chen-Xian Kong ₂ , Wen Chen ₂ , Lu Wang ₁ , Shao-Bin Zhi ₁ , Hong-Wei Sun ₁ , Yu-Chun Huang ₁ , Guo-Yu Chen ₄ , Hong-Bo Xin ₅ , Ke-Yu Deng ₅

Affiliation

肝脏缺血再灌注损伤（HIRI）经常发生在肝脏手术中，例如部分肝切除和肝移植，其中髓系巨噬细胞介导的炎症发挥着关键作用。细胞分裂周期 42 (Cdc42) 调节细胞迁移、细胞骨架重排和细胞极性。在本研究中，我们探讨了骨髓 Cdc42 在 HIRI 中的作用。在骨髓 Cdc42 敲除 (Cdc42) 和 Cdc42 小鼠中建立小鼠 HIRI 模型，缺血 1 小时，然后再灌注 12 小时。在 LyzCre 介导的切除下，用 Rosa 荧光报告基因追踪骨髓来源的巨噬细胞。进行了血清或肝酶活性、组织学和免疫学分析、基因表达、流式细胞术分析和细胞因子抗体阵列的实验。 Cdc42 的髓系缺失显着减轻了小鼠 HIRI 后的肝损伤，减少了肝坏死和炎症，并保留了肝功能。髓系Cdc42缺陷抑制髓系巨噬细胞的浸润，减少促炎细胞因子的分泌，抑制肝脏中髓系巨噬细胞的M1极化，促进M2极化。此外，Cdc42的失活通过抑制髓系巨噬细胞中STAT1的磷酸化并促进STAT3和STAT6的磷酸化来促进M2极化。此外，用 Cdc42 抑制剂 ML141 预处理也可以保护小鼠免受肝脏缺血再灌注损伤。抑制或缺失髓系 Cdc42 可通过抑制髓系巨噬细胞的浸润、抑制促炎反应和促进巨噬细胞中的 M2 极化来保护肝脏免受 HIRI 的影响。

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Myeloid Deletion of Cdc42 Protects Liver From Hepatic Ischemia-Reperfusion Injury via Inhibiting Macrophage-Mediated Inflammation in Mice

Hepatic ischemia-reperfusion injury (HIRI) often occurs in liver surgery, such as partial hepatectomy and liver transplantation, in which myeloid macrophage-mediated inflammation plays a critical role. Cell division cycle 42 (Cdc42) regulates cell migration, cytoskeleton rearrangement, and cell polarity. In this study, we explore the role of myeloid Cdc42 in HIRI. Mouse HIRI models were established with 1-hour ischemia followed by 12-hour reperfusion in myeloid Cdc42 knockout (Cdc42) and Cdc42 mice. Myeloid-derived macrophages were traced with Rosa fluorescent reporter under LyzCre-mediated excision. The experiments for serum or hepatic enzymic activities, histologic and immunologic analysis, gene expressions, flow cytometry analysis, and cytokine antibody array were performed. Myeloid deletion of Cdc42 significantly alleviated hepatic damages with the reduction of hepatic necrosis and inflammation, and reserved hepatic functions following HIRI in mice. Myeloid Cdc42 deficiency suppressed the infiltration of myeloid macrophages, reduced the secretion of proinflammatory cytokines, restrained M1 polarization, and promoted M2 polarization of myeloid macrophages in livers. In addition, inactivation of Cdc42 promoted M2 polarization via suppressing the phosphorylation of STAT1 and promoting phosphorylation of STAT3 and STAT6 in myeloid macrophages. Furthermore, pretreatment with Cdc42 inhibitor, ML141, also protected mice from hepatic ischemia-reperfusion injury. Inhibition or deletion of myeloid Cdc42 protects liver from HIRI via restraining the infiltration of myeloid macrophages, suppressing proinflammatory response, and promoting M2 polarization in macrophages.

更新日期：2024-02-09

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