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

  title={S100-alarmin-induced innate immune programming protects newborn infants from sepsis},
  author={Thomas Ulas and Sabine Pirr and Beate Fehlhaber and Marie S Bickes and Torsten G. Loof and Thomas Vogl and Lara Mellinger and Anna S. Heinemann and Johanna Burgmann and Jennifer Schöning and Sabine Schreek and Sandra Pfeifer and Friederike Reuner and Lena V{\"o}llger and Martin Stanulla and Maren von K{\"o}ckritz-Blickwede and Shirin Glander and Katarzyna Barczyk-Kahlert and Constantin von Kaisenberg and Judith Friesenhagen and Lena Fischer-Riepe and Stefanie Zenker and Joachim L. Schultze and Johannes Roth and Dorothee Viemann},
  journal={Nature Immunology},
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… 
S100-Alarmins Are Essential Pilots of Postnatal Innate Immune Adaptation
How infants are provided with S100-alarmins and why these allow an uneventful clash between the innate immune system and the extrauterine world are summarized.
Immunometabolic approaches to prevent, detect, and treat neonatal sepsis
Characterizing the ontogeny of immunometabolism will offer new opportunities to prevent, diagnose, and treat neonatal sepsis and define alterations in metabolic signatures as they change during ontogenY and as perturbed by immunization or infection.
Monocytes in Neonatal Bacterial Sepsis: Think Tank or Workhorse?
Clinical studies have shown that exposure to inflammation puts neonates at a high risk for adverse pulmonary, immunological and other organ developments, which may result in multiorgan disease.
Energy Demands of Early Life Drive a Disease Tolerant Phenotype and Dictate Outcome in Neonatal Bacterial Sepsis
Taking into account the central role of metabolism in the host response to infection and the severe metabolic demands of early life, it emerges that the striking clinical susceptibility to bacterial infection of the newborn is at its core a problem of metabolism.
Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation
Downregulation of two major transcriptional factors, early growth response gene (Egr)-2 and growth factor independence 1 (Gfi1), were identified to play a role in the exaggerated pro-inflammatory response of preterm MФ to LPS insult after priming with 65% or 3% O2.
Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future
A summary of studies that characterize immune ontogeny and neonatal sepsis is presented, followed by discussion of clinical trials assessing interventions such as breast milk, lactoferrin, probiotics, and pentoxifylline.
Impaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats
A metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis is shown and might be dependent on S100A8/A9 expression.
Constitutive TNF‐α signaling in neonates is essential for the development of tissue‐resident leukocyte profiles at barrier sites
  • Marie S Bickes, S. Pirr, D. Viemann
  • Biology, Medicine
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2019
It is demonstrated that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF‐α, which suggests that constitutive TNF—mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.
High Amounts of S100-Alarmins Confer Antimicrobial Activity on Human Breast Milk Targeting Pathogens Relevant in Neonatal Sepsis
The enteral supply of bioavailable, antimicrobially active amounts of S100-alarmins might be a promising option to protect newborns at high risk from infections and sepsis.
Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice.
The presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum, suggesting that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.


Hyper innate responses in neonates lead to increased morbidity and mortality after infection
It is shown that T cells are sufficient and necessary to control the early inflammatory response to LPS and that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection.
TRIF-Dependent Innate Immune Activation Is Critical for Survival to Neonatal Gram-Negative Sepsis
A differential requirement for the survival of neonates versus adults to Gram-negative infection, and that modulation of TRIF in neonates can be used to augment survival to neonatal sepsis are suggested.
Critical Role for CXC Ligand 10/CXC Receptor 3 Signaling in the Murine Neonatal Response to Sepsis
A critical role is suggested for CXCL10 signaling during neonatal sepsis, which worsens not only recruitment and phagocytic function of peritoneal granulocytes and macrophages but also survival and the protective adjuvant effect of pretreatment with a Toll-like receptor 4 agonist is demonstrated.
Type I IFN Modulates Host Defense and Late Hyperinflammation in Septic Peritonitis1
Critical functions of the type I IFN pathway during severe mixed bacterial infections leading to sepsis are revealed and it is suggested that type IIFN exerts predominantly adverse effects under these conditions.
Innate immunity of the newborn: basic mechanisms and clinical correlates
  • O. Levy
  • Medicine, Biology
    Nature Reviews Immunology
  • 2007
Invention of innate immunity in newborns is described and how this knowledge might be used to prevent and treat infection in this vulnerable population is discussed.
Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis
Future therapeutic approaches may need to be tailored to the timing of the infectious event based on postnatal age because of significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations.
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
The epigenetic and transcriptional programs of monocyte differentiation to macrophages that distinguish tolerant and trained macrophage phenotypes are uncovered, providing a resource to further understand and manipulate immune-mediated responses.
Mechanisms Establishing TLR4-Responsive Activation States of Inflammatory Response Genes
Comprehensive genome-wide analysis of the epigenetic and transcription status of the TLR4-induced transcriptional program in macrophages suggests that Toll-like receptor 4 (TLR4)-dependent activation of nearly all immediate/early- and late-response genes results from a sequential process in which signal-independent factors initially establish basal levels of gene expression that are then amplified by signal-dependent transcription factors.