Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.
Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.
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训练有素的免疫诱导通过增强炎症反应和抗菌活性来保护新生小鼠免受微生物败血症
DOI：
10.2147/jir.s363995
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发表时间：
2022
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
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作者：
新生儿易受各种微生物感染，并有很高的风险发展为严重败血症和感染性休克。出现的证据表明，诱导训练的免疫在成年单核细胞/巨噬细胞中触发更强的炎症反应，从而提供针对微生物感染的保护。本研究旨在研究训练后的免疫力是否可诱导，并发挥其对新生儿微生物败血症的保护作用。卡介苗（BCG）加细菌脂蛋白（BLP）诱导训练免疫保护新生小鼠免受盲肠浆液性腹膜炎诱导的多微生物败血症，这种保护与循环炎性细胞因子升高、中性粒细胞募集增加和细菌清除加速有关。BCG+BLP体外刺激新生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，其特征在于在靶向炎症和抗微生物基因的启动子处具有增强的H3 K4 me 3、H3 K27 Ac和抑制的H3 K9 me 3的组蛋白修饰。关键的是，BCG+BLP刺激导致细胞代谢的转变，糖酵解增加，这是随后BCG+ BLP触发的表观遗传重编程和增强炎症反应和抗微生物能力的先决条件。这些结果表明，BCG+BLP诱导新生儿训练免疫力，从而通过增强炎症和抗菌反应来保护免受微生物感染。
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.