Complement Inhibition Alleviates Cholestatic Liver Injury Through Mediating Macrophage Infiltration and Function in Mice.
Complement Inhibition Alleviates Cholestatic Liver Injury Through Mediating Macrophage Infiltration and Function in Mice.
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DOI：
10.3389/fimmu.2021.785287
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发表时间：
2021
影响因子：
7.3
通讯作者：
He S
中科院分区：
文献类型：
--
作者：
Guo Z;Chen J;Zeng Y;Wang Z;Yao M;Tomlinson S;Chen B;Yuan G;He S
胆汁淤积性肝损伤（CLI）与炎症反应和氧化应激相关，是术后并发症的严重危险因素。补体系统参与广泛的肝脏疾病，包括胆汁淤积。本研究评估了补体在CLI中的作用以及靶向补体抑制剂CR2-Crry在CLI中的治疗效果。野生型和补体基因缺陷小鼠采用胆总管结扎（BDL）诱导CLI或假手术，然后用CR2-Crry或GdCl3治疗。通过生化分析、流式细胞术、免疫组织化学、ELISA和定量RT-PCR研究补体在CLI中的作用和CR2-Crry的潜在治疗作用。C3缺乏和CR2-Crry可显著减轻CLI小鼠的肝损伤，并显著降低肝脏中中性粒细胞和巨噬细胞的数量。C3缺乏和CR2-Crry也显著降低中性粒细胞Mac-1的表达和肝脏VCAM-1的表达。更重要的是，C3缺乏和CR2-Crry显著抑制了这些小鼠的M1巨噬细胞极化。静脉注射GdCl3抑制肝脏巨噬细胞的浸润和活化。但肝损伤明显加重。BDL可显著提高门静脉血中脂多糖（LPS）水平，但对外周血无显著影响。GdCl3显著增加外周血LPS，提示巨噬细胞清除门静脉血LPS。口服氨苄西林对GdCl3处理的小鼠降低门静脉血液中的LPS水平，减轻肝损伤。相反，腹腔注射LPS增加门静脉血LPS，逆转氨苄西林的保护作用。有趣的是，C3缺乏并不影响LPS的清除。补体参与CLI，可能介导肝脏中性粒细胞和巨噬细胞M1极化的浸润和激活。C3缺乏和CR2-Crry可显著缓解CLI。抑制补体可保持巨噬细胞清除LPS的保护功能，提示补体抑制可能有助于治疗CLI。
Cholestatic liver injury (CLI), which is associated with inflammatory reactions and oxidative stress, is a serious risk factor for postoperative complications. Complement system is involved in a wide range of liver disorders, including cholestasis. The present study assessed the role of complement in CLI and the therapeutic effect of the site-targeted complement inhibitor CR2-Crry in CLI. Wild-type and complement gene deficient mice underwent common bile duct ligation (BDL) to induce CLI or a sham operation, followed by treatment with CR2-Crry or GdCl3. The roles of complement in CLI and the potential therapeutic effects of CR2-Crry were investigated by biochemical analysis, flow cytometry, immunohistochemistry, ELISA, and quantitative RT-PCR. C3 deficiency and CR2-Crry significantly reduced liver injuries in mice with CLI, and also markedly decreasing the numbers of neutrophils and macrophages in the liver. C3 deficiency and CR2-Crry also significantly reduced neutrophil expression of Mac-1 and liver expression of VCAM-1. More importantly, C3 deficiency and CR2-Crry significantly inhibited M1 macrophage polarization in these mice. Intravenous injection of GdCl3 inhibited macrophage infiltration and activation in the liver. However, the liver injury increased significantly. BDL significantly increased the level of lipopolysaccharide (LPS) in portal blood, but not in peripheral blood. GdCl3 significantly increased LPS in peripheral blood, suggesting that macrophages clear portal blood LPS. Oral administration of ampicillin to in GdCl3 treated mice reduced LPS levels in portal blood and alleviated liver damage. In contrast, intraperitoneal injection LPS increased portal blood LPS and reversed the protective effect of ampicillin. Interestingly, C3 deficiency did not affect the clearance of LPS. Complement is involved in CLI, perhaps mediating the infiltration and activation of neutrophils and macrophage M1 polarization in the liver. C3 deficiency and CR2-Crry significantly alleviated CLI. Inhibition of complement could preserve the protective function of macrophages in clearing LPS, suggesting that complement inhibition could be useful in treating CLI.