This study describes an important role for the endogenous alarmins S100A8 and S100A9 in protecting newborn infants from sepsis. Healthy newborns produce extremely high levels of S100 alarmins for the first five days of life; the authors found that these alarmins signal through TLR4 to preactivate MYD88-dependent (but not TRIF-dependent) genes in neonatal monocytes, leaving them refractory to subsequent activation of MYD88. This 'rewiring' of neonatal monocytes prevented hyperinflammatory responses to bacteria without compromising host immunity. In a mouse model of Staphylococcus aureus-induced sepsis, S100A9-deficient neonates produced increased levels of pro-inflammatory cytokines, leading to fatal sepsis. In humans, pre-term infants that experienced late-onset neonatal sepsis had lower cord blood levels of S100 alarmins.
Ulas, T. et al. S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat. Immunol. 18, 622–632 (2017)
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Bordon, Y. Alarmins rewire innate immunity in newborns. Nat Rev Immunol 17, 467 (2017). https://doi.org/10.1038/nri.2017.84