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Imbalanced Inflammatory Responses in Preterm and Term Cord Blood Monocytes and Expansion of the CD14+CD16+ Subset
Kirsten Glaser1, David Kern2, Christian P Speer2
1Center for Pediatric Research Leipzig, Division of Neonatology, Department of Women's and Children's Health, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Insights
Infant monocytes show strong pro-inflammatory and weak anti-inflammatory responses, leading to higher cytokine imbalance. This may contribute to infection risk in newborns, with intermediate monocytes playing a key role.
Area of Science:
- Immunology
- Neonatal Medicine
Background:
- Innate immunity in preterm and term infants presents unique challenges for infection and inflammation-related morbidity.
- Mechanisms underlying infant immune responses, particularly monocyte function and toll-like receptor (TLR) signaling, require further elucidation.
Purpose of the Study:
- To compare pro- and anti-inflammatory cytokine production and monocyte subset responses in preterm and term infant cord blood (CB) monocytes versus adult controls.
- To investigate the impact of various TLR pathway stimulations on these immune responses.
Main Methods:
- Assessed mRNA and protein expression of cytokines in CB monocytes from preterm and term infants and adult controls.
- Stimulated monocytes ex vivo with ligands for TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9.
- Analyzed monocyte subset frequencies, TLR expression, and phosphorylation of signaling molecules.
Main Results:
- Term infant monocytes exhibited pro-inflammatory responses comparable to adults; preterm infant monocytes showed lower IL-1β.
- Both preterm and term infant monocytes produced less anti-inflammatory IL-10 and IL-1ra, resulting in higher pro-inflammatory to anti-inflammatory cytokine ratios.
- Stimulated CB monocytes displayed increased intermediate monocyte (CD14+CD16+) frequencies, particularly with TLR1/2, TLR2/6, and TLR4 stimulation.
Conclusions:
- Cord blood monocytes from both preterm and term infants demonstrate robust pro-inflammatory and attenuated anti-inflammatory responses, leading to imbalanced cytokine profiles.
- The expansion of the intermediate monocyte subset, known for pro-inflammatory characteristics, may contribute to the heightened inflammatory state observed in neonates.
Abstract:
Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes-except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14+CD16+). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.
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