Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition
Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition
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Csf2 通过促进替代性巨噬细胞转变减轻脓毒症引起的急性肾损伤
DOI：
10.3389/fimmu.2020.01415
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发表时间：
2020-07-07
影响因子：
7.3
通讯作者：
Peng, Zhiyong
中科院分区：
文献类型：
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作者：
Li, Yiming;Zhai, Pan;Peng, Zhiyong
脓毒症是一种全身性炎症状态，发生在感染和显著增加死亡率与急性肾损伤（阿基）的组合。巨噬细胞在损伤后在肾脏中积累，并经历从促炎（M1）表型到正常修复所需的交替激活（M2）表型的转变。然而，在体内调节从M1到M2表型转变的特定信号是未知的。在这里，我们发现了一个意想不到的作用，集落刺激因子2（Csf 2）在控制巨噬细胞转化在体外和盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型。我们首先将人M1巨噬细胞与HK-2细胞共培养，并通过Luminex表征细胞因子/趋化因子谱。与单独培养的M1巨噬细胞相比，M1巨噬细胞与人肾-2（HK-2）细胞共培养的培养基中过表达的细胞因子和趋化因子中，Csf 2和IL 6显示出最大的增加。Csf 2仅由HK-2细胞分泌，而不被M1巨噬细胞分泌。此外，重组人Csf 2蛋白以剂量和时间依赖性方式促进M1巨噬细胞向M2表型的转变。M1巨噬细胞诱导的HK-2细胞凋亡和活性氧（ROS）释放在外源性Csf 2作用后减弱。此外，从促炎性M1表型到M2表型的转换通过p-Stat 5途径发生，该途径由Csf 2激活。重要的是，我们发现CLP后腹腔注射Csf 2中和抗体加重了肾损伤并抑制了肾小管增殖，随后降低了存活率。然而，施用重组小鼠Csf 2蛋白可以拯救脓毒症小鼠。总之，我们的研究结果表明，Csf 2通过激活p-STAT 5在调节巨噬细胞转化中起着关键作用。这些数据形成了一个基础，在此基础上，可以设计新的治疗策略，以提高基于苦参碱的治疗脓毒症诱导的阿基的疗效。
Sepsis is a systemic inflammatory state that occurs in response to infection and significantly increases mortality in combination with acute kidney injury (AKI). Macrophages accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1) phenotype to an alternatively activated (M2) phenotype that is required for normal repair. However, the specific signals that regulate the transition from the M1 to M2 phenotype in vivo are unknown. Here, we found an unexpected role of Colony stimulating factor 2 (Csf2) in controlling macrophage transition in vitro and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). We first co-cultured human M1 macrophages with HK-2 cells and characterized cytokine/chemokine profiles via Luminex. Of the cytokines and chemokines that were overexpressed in medium from M1 macrophages cocultured with human kidney-2 (HK-2) cells compared with that from M1 macrophages cultured alone, Csf2 and IL6 showed the greatest increases. Csf2 was exclusively secreted by HK-2 cells but not by M1 macrophages. Furthermore, recombinant human Csf2 protein promoted transition of M1 macrophages to the M2 phenotype in a dose and time-dependent manner. The apoptosis and reactive oxygen species (ROS) release induced by M1 macrophages in HK-2 cells was attenuated after exposure to exogenous Csf2. In addition, the switch from the proinflammatory M1 phenotype to the M2 phenotype occurred via the p-Stat5 pathway, which was activated by Csf2. Importantly, we found that intraperitoneal injection of a Csf2-neutralizing antibody after CLP aggravated kidney injury and suppressed tubular proliferation, subsequently decreasing survival. However, administration of recombinant mouse Csf2 protein could rescue mice with sepsis. Together, our results indicate that Csf2 plays critical roles in regulating macrophage transition via activation of p-STAT5. These data form a foundation upon which new therapeutic strategies can be designed to improve the therapeutic efficacy of cytokine-based treatments for sepsis-induced AKI.