Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation

TY - JOUR

T1 - Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation

AU - Twisselmann, Nele

AU - Pagel, Julia

AU - Künstner, Axel

AU - Weckmann, Markus

AU - Hartz, Annika

AU - Glaser, Kirsten

AU - Hilgendorff, Anne

AU - Göpel, Wolfgang

AU - Busch, Hauke

AU - Herting, Egbert

AU - Weinberg, Jason B

AU - Härtel, Christoph

N1 - Copyright © 2021 Twisselmann, Pagel, Künstner, Weckmann, Hartz, Glaser, Hilgendorff, Göpel, Busch, Herting, Weinberg and Härtel.

PY - 2021

Y1 - 2021

N2 - Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O2) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O2 = 65%) or hypoxia (O2 = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O2, subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O2 together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. 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. Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.

AB - Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O2) and infections. We hypothesized that dysregulated macrophage (MФ) activation is a key feature leading to inflammation-mediated development of bronchopulmonary dysplasia (BPD) in preterm infants. Therefore, we aimed to determine age-dependent differences in immune responses of monocyte-derived MФ comparing cord blood samples derived from preterm (n=14) and term (n=19) infants as well as peripheral blood samples from healthy adults (n=17) after lipopolysaccharide (LPS) exposure. Compared to term and adult MФ, LPS-stimulated preterm MФ showed an enhanced and sustained pro-inflammatory immune response determined by transcriptome analysis, cytokine release inducing a RORC upregulation due to T cell polarization of neonatal T cells, and TLR4 surface expression. In addition, a double-hit model was developed to study pulmonary relevant exposure factors by priming MФ with hyperoxia (O2 = 65%) or hypoxia (O2 = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O2, subsequent LPS stimulation in preterm MФ led to an exaggerated pro-inflammatory response (e.g. increased HLA-DR expression and cytokine release) compared to LPS stimulation alone. Both, exposure to 65% or 3% O2 together with subsequent LPS stimulation, resulted in an exaggerated pro-inflammatory response of preterm MФ determined by transcriptome analysis. 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. Preterm MФ responses to LPS and hyperoxia/hypoxia suggest their involvement in excessive inflammation due to age-dependent differences, potentially mediated by downregulation of Egr2 and Gfi1 in the developing lung.

KW - Adult

KW - Bronchopulmonary Dysplasia/etiology

KW - Cytokines/biosynthesis

KW - Female

KW - Gene Expression Profiling

KW - Gestational Age

KW - Humans

KW - Infant, Newborn

KW - Infant, Premature/immunology

KW - Inflammation/etiology

KW - Lipopolysaccharides/pharmacology

KW - Macrophages/drug effects

KW - Male

KW - Oxygen/pharmacology

KW - Toll-Like Receptor 4/physiology

U2 - 10.3389/fimmu.2021.762789

DO - 10.3389/fimmu.2021.762789

M3 - SCORING: Journal article

C2 - 34868007

VL - 12

SP - 762789

JO - FRONT IMMUNOL

JF - FRONT IMMUNOL

SN - 1664-3224

ER -