High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates
High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates
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DOI：
10.1073/pnas.1514018113
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
T. Roger;A. Schneider;M. Weier;F. Sweep;D. Le Roy;J. Bernhagen;T. Calandra;E. Giannoni
中科院分区：
文献类型：
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作者：
T. Roger;A. Schneider;M. Weier;F. Sweep;D. Le Roy;J. Bernhagen;T. Calandra;E. Giannoni
在怀孕期间，高水平的腺苷和肾上腺素循环降低胎儿免疫细胞的能力，安装强大的促炎反应。与此相反，新生儿表达的促炎性免疫调节迁移抑制因子（MIF）水平比成人高10倍。MIF维持细胞活化和细胞因子产生，并在新生儿单核细胞中反调节腺苷和前列腺素E2介导的免疫抑制。然而，在已建立的感染过程中，MIF的过度表达会影响新生小鼠的结局。因此，我们确定了MIF在调节新生儿先天免疫反应中的独特作用，并提出MIF具有保护作用，以降低新生儿期对感染的易感性，但可能有利于败血症期间不受控制的炎症，导致不良后果。新生儿易受感染与有效免疫应答能力有限有关。胎儿和新生儿循环中高浓度的腺苷和甘草素会阻碍新生儿免疫细胞的抗菌反应。然而，还没有研究是否存在抵消新生儿免疫抑制的机制。值得注意的是，巨噬细胞移动抑制因子（MIF），一种组成性表达的促炎性免疫调节细胞因子的循环水平，在新生儿中比儿童和成人高10倍。新生儿单核细胞表达高水平的MIF，并释放MIF刺激大肠杆菌和B组链球菌，早发性新生儿败血症的主要病原体。抑制MIF活性或MIF表达可减少微生物产物诱导的p38和ERK 1/2促分裂原活化蛋白激酶磷酸化和细胞因子分泌。在新生儿中使用重组MIF，而不是成人浓度，逆转腺苷和前列腺素E2介导的对暴露于E.杆菌与一旦感染建立高水平的MIF对宿主有害的概念一致，用MIF的小分子抑制剂治疗降低了全身炎症反应、细菌增殖和败血症新生小鼠的死亡率。总而言之，这些数据为新生儿如何科普免疫抑制环境以维持一定的先天防御阈值提供了一个机械解释。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治疗的潜在有吸引力的靶点。
Significance During pregnancy, high circulating levels of adenosine and prostaglandins reduce the ability of fetal immune cells to mount powerful proinflammatory responses. In contrast, newborns express 10-fold higher levels of the proinflammatory immune regulator migration inhibitory factor (MIF) compared with adults. MIF sustains cell activation and cytokine production and counterregulates adenosine and prostaglandin E2-mediated immunosuppression in newborn monocytes. Yet excessive MIF expression during an established infection worsens the outcome of newborn mice. Thus, we identify a unique role for MIF in regulating neonatal innate immune responses and propose that MIF has a protective role to reduce susceptibility to infection during the neonatal period but may favor uncontrolled inflammation during sepsis, leading to adverse outcomes. 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.