TY  - JOUR
A1  - Twisselmann, Nele
A1  - Pagel, Julia
A1  - Künstner, Axel
A1  - Weckmann, Markus
A1  - Hartz, Annika
A1  - Glaser, Kirsten
A1  - Hilgendorff, Anne
A1  - Göpel, Wolfgang
A1  - Busch, Hauke
A1  - Herting, Egbert
A1  - Weinberg, Jason B.
A1  - Härtel, Christoph
T1  - Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation
JF  - Frontiers in Immunology
N2  - Preterm infants are highly susceptible to sustained lung inflammation, which may be triggered by exposure to multiple environmental cues such as supplemental oxygen (O\(_2\)) 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 (O\(_2\) = 65%) or hypoxia (O\(_2\) = 3%) followed by lipopolysaccharide (LPS, 100ng/ml). When primed by 65% O\(_2\), 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% O\(_2\) 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% O\(_2\). 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  - preterm infants
KW  - sustained inflammation
KW  - macrophages
KW  - hyperoxia
KW  - hypoxia
KW  - infection
KW  - bronchopulmonary dysplasia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250356
SN  - 1664-3224
VL  - 12
ER  - 
TY  - JOUR
A1  - Pagel, Julia
A1  - Twisselmann, Nele
A1  - Rausch, Tanja K.
A1  - Waschina, Silvio
A1  - Hartz, Annika
A1  - Steinbeis, Magdalena
A1  - Olbertz, Jonathan
A1  - Nagel, Kathrin
A1  - Steinmetz, Alena
A1  - Faust, Kirstin
A1  - Demmert, Martin
A1  - Göpel, Wolfgang
A1  - Herting, Egbert
A1  - Rupp, Jan
A1  - Härtel, Christoph
T1  - Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants
JF  - Frontiers in Immunology
N2  - Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 382; 23 + 0 – 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall naïve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.
KW  - regulatory T cells
KW  - Tregs
KW  - bronchopulmonary dysplasia
KW  - BPD
KW  - preterm infant
KW  - neonate
KW  - Foxp3
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212409
SN  - 1664-3224
VL  - 11
ER  -