Roger Thierry, Schneider Anina, Weier Manuela, Sweep Fred C G J, Le Roy Didier, Bernhagen Jürgen, Calandra Thierry, Giannoni Eric
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; Service of Neonatology, Department of Pediatrics, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland;
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E997-1005. doi: 10.1073/pnas.1514018113. Epub 2016 Feb 8.
The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.
新生儿易受感染与产生有效免疫反应的能力有限有关。胎儿和新生儿循环中高浓度的腺苷和前列腺素会阻碍新生儿免疫细胞的抗菌反应。然而，尚未对抵消新生儿免疫抑制的机制进行研究。值得注意的是，巨噬细胞移动抑制因子（MIF）是一种组成性表达的促炎免疫调节细胞因子，其在新生儿中的循环水平比儿童和成人高10倍。新生儿单核细胞表达高水平的MIF，并在受到大肠杆菌和B族链球菌（早发型新生儿败血症的主要病原体）刺激后释放MIF。抑制MIF活性或MIF表达可降低微生物产物诱导的p38和ERK1/2丝裂原活化蛋白激酶的磷酸化以及细胞因子的分泌。以新生儿而非成人浓度使用的重组MIF可对抗腺苷和前列腺素E2介导的对暴露于大肠杆菌的新生儿单核细胞中ERK1/2激活和TNF产生的抑制作用。与一旦感染确立高水平的MIF对宿主有害的概念一致，用MIF小分子抑制剂治疗可降低败血症新生小鼠的全身炎症反应、细菌增殖和死亡率。总之，这些数据为新生儿如何应对免疫抑制环境以维持一定的先天防御阈值提供了机制解释。然而，在严重感染的情况下，相同的防御机制可能以宿主为代价，这表明MIF可能是新生儿败血症免疫调节辅助治疗的一个潜在有吸引力的靶点。
