Zhou Huiting, Lu Xiaying, Huang Jie, Jordan Patrick, Ma Shurong, Xu Lingqi, Hu Fangjie, Gui Huan, Zhao He, Bai Zhenjiang, Redmond H Paul, Wang Jiang Huai, Wang Jian
Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, People's Republic of China.
Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
J Inflamm Res. 2022 Jul 7;15:3829-3845. doi: 10.2147/JIR.S363995. eCollection 2022.
Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection.
This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates.
Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity.
These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.
新生儿易受多种微生物感染，发生严重脓毒症和脓毒性休克的风险很高。新出现的证据表明，诱导训练有素的免疫会在成年单核细胞/巨噬细胞中引发更强的炎症反应，从而提供针对微生物感染的保护。
本研究旨在探讨训练有素的免疫在新生儿中是否可诱导，并对微生物脓毒症发挥保护作用。
用卡介苗（BCG）加细菌脂蛋白（BLP）诱导训练有素的免疫可保护新生小鼠免受盲肠灌洗液诱导的多微生物脓毒症，这种保护作用与循环炎症细胞因子升高、中性粒细胞募集增加和细菌清除加速有关。用BCG+BLP体外刺激新生小鼠巨噬细胞可增强炎症反应和抗菌活性。值得注意的是，BCG+BLP刺激导致表观遗传重塑，其特征是组蛋白修饰，在靶向炎症和抗菌基因的启动子处H3K4me3、H3K27Ac增强，H3K9me3受到抑制。至关重要的是，BCG+BLP刺激导致细胞代谢发生转变，糖酵解增加，这是随后BCG+BLP触发的表观遗传重编程以及增强炎症反应和抗菌能力的先决条件。
这些结果表明，BCG+BLP可在新生儿中诱导训练有素的免疫，从而通过增强炎症和抗菌反应来预防微生物感染。
