Background Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast Growth Factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined. Methods A cecal ligation and puncture (CLP) -induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples. Results FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis from ICU were significantly higher than those in healthy controls. Conclusions These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis.

中文翻译：

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FGF8 通过增强宿主的抗感染免疫来预防多种微生物脓毒症


背景 脓毒症的特征是由宿主对感染的反应不平衡引起的危及生命的综合征。成纤维细胞生长因子 8 （FGF8） 已被新发现在炎症和先天免疫中发挥重要作用，但其在宿主对脓毒症的反应中的作用尚不清楚。方法 建立盲肠结扎穿刺 （CLP） 诱导的小鼠脓毒症模型，评价 FGF8 在脓毒症过程中的免疫调节功能。使用相关分子生物学实验的细胞模型阐明了潜在的分子机制。使用临床样本评价 FGF8 在脓毒症辅助诊断中的临床价值。结果 与对照组相比，CLP 诱导的脓毒症小鼠的 FGF8 蛋白浓度升高。在体内，使用抗 FGF8 抗体阻断 FGF8 显着增加了死亡率和细菌负荷，并且与 CLP 后组织损伤的显著加重平行。重组 FGF8 （rFGF8） 的治疗性给药以 FGFR1 依赖性方式改善了脓毒症小鼠的细菌清除率和死亡率。在体外，FGF8 通过增强 ERK1/2 信号通路的磷酸化直接增强细菌吞噬作用和对巨噬细胞的杀伤，这可以用 ERK1/2 通路抑制剂 U0126 消除。临床上，ICU 脓毒症成人和儿童患者的血清 FGF8 水平均显著高于健康对照者。结论 这些结果揭示了 FGF8 在通过增强宿主免疫防御来提高脓毒症存活率方面以前未被认识的作用。因此，靶向 FGF8 可能为脓毒症的诊断和免疫治疗提供新的策略。