S100-alarmin-induced innate immune programming protects newborn infants from sepsis
S100-alarmin-induced innate immune programming protects newborn infants from sepsis
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DOI：
10.1038/ni.3745
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发表时间：
2017-06-01
影响因子：
30.5
通讯作者：
Viemann, Dorothee
中科院分区：
文献类型：
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作者：
Ulas, Thomas;Pirr, Sabine;Viemann, Dorothee
新生儿败血症死亡的高风险被认为是由先天免疫细胞的反应受损引起的;然而，新生儿败血症的过度炎症过程的临床观察与这一概念相矛盾。使用转录组学，表观遗传学和免疫学方法，我们证明了大量的围产期alarmins S100 A8和S100 A9特异性改变MyD 88依赖性促炎基因程序。S100编程可以防止过度炎症反应，而不会损害病原体防御。TRIF-适配器依赖性调控基因不受围产期S100编程的影响，对脂多糖反应强烈，但几乎没有表达。TRIF依赖基因的稳态表达在人类新生儿生命的第一年仅逐渐增加，将免疫调节转向成人表型。这种短暂的alarmin编程的关键序列的破坏和随后的调节途径的重编程增加了炎症过度和脓毒症的风险。总的来说，这些数据表明，新生儿的特点是选择性的，短暂的微生物无反应性，防止有害的过度炎症在微妙的新生儿，同时允许足够的免疫保护。
The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense. TRIF-adaptor-dependent regulatory genes remained unaffected by perinatal S100 programming and responded strongly to lipopolysaccharide, but were barely expressed. Steady-state expression of TRIF-dependent genes increased only gradually during the first year of life in human neonates, shifting immune regulation toward the adult phenotype. Disruption of this critical sequence of transient alarmin programming and subsequent reprogramming of regulatory pathways increased the risk of hyperinflammation and sepsis. Collectively these data suggest that neonates are characterized by a selective, transient microbial unresponsiveness that prevents harmful hyperinflammation in the delicate neonate while allowing for sufficient immunological protection.