In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock

  title={In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock},
  author={Anna S. Heinemann and Sabine Pirr and Beate Fehlhaber and Lara Mellinger and Johanna Burgmann and Mandy Busse and Marco Ginzel and Judith Friesenhagen and Maren von K{\"o}ckritz-Blickwede and Thomas Ulas and Constantin S. Kaisenberg and Johannes Roth and Thomas Vogl and Dorothee Viemann},
  journal={The FASEB Journal},
  pages={1153 - 1164}
The high susceptibility of newborn infants to sepsis is as cribed to animmaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid‐derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo‐MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo‐MDSCs have been… 
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.
Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation
The transitory presence of MDSCs may be critical for regulation of inflammation in newborns and played a critical role in control of experimental necrotizing enterocolitis in newborn mice.
Group B streptococci infection model shows decreased regulatory capacity of cord blood cells
It is demonstrated that cord blood T cells exhibited increased proliferative capacity after stimulation with group B streptococci (GBS) in comparison to adult T cells, which may contribute to prolonged inflammation and development of post-inflammatory diseases in newborns.
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.
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.
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.
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.
S100A8/A9 is the first predictive marker for neonatal sepsis
Serum S100A8/A9 proved as an independent predictive marker of late-onset neonatal sepsis (LOS) in preterm infants, which for the first time offers the opportunity to change current treatment policies by improving antibiotic stewardship and timely individualized therapeutic intervention.
Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis
This study reveals a hitherto unrecognized mechanism of pediatric sepsis susceptibility and suggests that NETs represents a potential target to improve clinical outcomes of sepsi.
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.


Loss of S100A9 (MRP14) Results in Reduced Interleukin-8-Induced CD11b Surface Expression, a Polarized Microfilament System, and Diminished Responsiveness to Chemoattractants In Vitro
The data suggest that loss of the calcium-binding S100A9 protein reduces the responsiveness of the neutrophils upon chemoattractant stimuli at least in vitro, which may be responsible for the lack of any effect in the two in vivo models the authors have investigated so far.
Granulocytic myeloid derived suppressor cells expand in human pregnancy and modulate T‐cell responses
It is demonstrated that MDSCs with a granulocytic phenotype (GR‐MDSCs) are highly increased in the peripheral blood of healthy pregnant women during all stages of pregnancy compared with nonpregnant controls, whereas numbers of monocytic M DSCs were unchanged.
Neutrophilic myeloid‐derived suppressor cells in cord blood modulate innate and adaptive immune responses
These studies establish neutrophilic Gr‐MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates and might represent a therapeutic target in neonatal infections.
Myeloid Derived Suppressor Cells Are Present at High Frequency in Neonates and Suppress In Vitro T Cell Responses
It is determined that these neonatal MDSC are of granulocytic origin (G-MDSC), and suppress both CD4+ and CD8+ T cell proliferative responses in a contact-dependent manner and gamma interferon production.
Myeloid-derived suppressor cells control microbial sepsis
New information is provided on the role of MDSCs, suggesting a protective effect during sepsis, and adoptive transfer of day 10 M DSCs to septic mice attenuated peritoneal cytokine production, increased bacterial clearance and dramatically improved survival rate.
MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis
This work identifies a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis and contributes to sepsi-induced T cell suppression and preferential Th2 polarization.
MyD 88-dependent expansion of an immature GR-1 + CD 11 b + population induces T cell suppression and Th 2 polarization in sepsis
The present study examined the role of immature myeloid cells in sepsis, as well as their contribution to the sepsi-induced defects in acquired immunity.
Acquisition of Adult-Like TLR4 and TLR9 Responses during the First Year of Life
The first year of life represents a critical period during which adult-like levels of TLR responses are reached for most but not all cytokine responses.
Induction of myelodysplasia by myeloid-derived suppressor cells.
It is reported that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis.
Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies
This study sets out to perform a direct comparative analysis across both granulocytic and monocytic MDSC subsets in terms of their frequency, absolute number, and function in the peripheral blood of patients with advanced GI cancer, and determines the optimal method of sample processing.