Imbalanced Inflammatory Responses in Preterm and Term Cord Blood Monocytes and Expansion of the CD14+CD16+ Subset upon Toll-like Receptor Stimulation
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Published:2023-03-03
Issue:5
Volume:24
Page:4919
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Glaser Kirsten1ORCID, Kern David2, Speer Christian P.2, Schlegel Nicolas3ORCID, Schwab Michael4, Thome Ulrich H.1ORCID, Härtel Christoph2, Wright Clyde J.5
Affiliation:
1. Center for Pediatric Research Leipzig, Division of Neonatology, Department of Women’s and Children’s Health, University of Leipzig Medical Center, 04103 Leipzig, Germany 2. Department of Pediatrics, University Hospital Würzburg, 97080 Würzburg, Germany 3. Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery, University of Würzburg, 97080 Würzburg, Germany 4. Department of Obstetrics and Gynecology, University of Würzburg, 97080 Würzburg, Germany 5. Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO 80045, USA
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.
Funder
Open Access Publishing Fund of Leipzig University
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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