S100-alarmin-induced innate immune programming protects newborn infants from sepsis

Abstract

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.

Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis

“…One possible mechanism is regulation of monocyte function through extrinsic factors either in cord plasma or from other mononuclear populations, which were removed in our experiments and those of Lissner et al . A variety of soluble mediators capable of modulating monocyte responses are present in plasma, including adenosine, the antimicrobial peptide LL‐37 and the alarmins S100A8/A9 . Ulas et al .…”

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…Human neonatal immune cells express innate immune receptors and respond to microbial exposure, albeit in a different manner compared with adult cells . In contrast to the murine gut epithelium, postnatal reprogramming of human monocytes was mediated by high perinatal serum concentrations of the endogenous TLR4 ligand S100A8/9 (calprotectin) . The S100A8/9 effect was also observed in cord blood macrophages mediated through inhibition of the mechanistic target of rapamycin pathway and associated with reduced glycolysis .…”

“…Consistently, dynamic transcriptomic and metabolic changes have been described in human peripheral blood cells during the first week after birth. In both murine enterocytes and blood monocytes, innate immune tolerance was associated with cellular reprogramming and expression of an alternative set of genes . It might, therefore, not only serve to reduce the susceptibility to inflammation but simultaneously to foster the establishment of a stable host–microbial interaction.…”

“…, left panel). Importantly, this innate immune tolerance is accompanied by transcriptional reprogramming, which may serve to provide some basic degree of mucosal and systemic antimicrobial host defense activation during the first days after birth . During this early time window, the initial bacterial colonization takes place.…”

Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation

“…This reduction in granulopoiesis is often characterized clinically in human preterm neonates by a neutropenic response to infection and sepsis [11]. Recently, it has been shown that the transcription pattern in monocytes from neonates during the first few days of life is opposite to the adult monocyte response after stimulation, with a strong induction of the Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-b (TRIF)-dependent regulatory genes, and a weak myeloid differentiation primary response 88 (MyD88)-dependent proinflammatory response induced mainly by the overproduction of S100 alarmins [13]. Conversely, monocytes and macrophages are also involved in the host protective response to sepsis, and these cells are immature in newborns [12].…”