Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation
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 dev...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.762789/full |
| _version_ | 1819003899334361088 |
|---|---|
| author | Nele Twisselmann Julia Pagel Julia Pagel Axel Künstner Markus Weckmann Markus Weckmann Annika Hartz Kirsten Glaser Anne Hilgendorff Wolfgang Göpel Hauke Busch Egbert Herting Jason B. Weinberg Jason B. Weinberg Christoph Härtel |
| author_facet | Nele Twisselmann Julia Pagel Julia Pagel Axel Künstner Markus Weckmann Markus Weckmann Annika Hartz Kirsten Glaser Anne Hilgendorff Wolfgang Göpel Hauke Busch Egbert Herting Jason B. Weinberg Jason B. Weinberg Christoph Härtel |
| author_sort | Nele Twisselmann |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T23:28:20Z |
| format | Article |
| id | doaj.art-91527cebc9414533b987b62eea36af52 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T23:28:20Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-91527cebc9414533b987b62eea36af522022-12-21T19:23:20ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.762789762789Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS StimulationNele Twisselmann0Julia Pagel1Julia Pagel2Axel Künstner3Markus Weckmann4Markus Weckmann5Annika Hartz6Kirsten Glaser7Anne Hilgendorff8Wolfgang Göpel9Hauke Busch10Egbert Herting11Jason B. Weinberg12Jason B. Weinberg13Christoph Härtel14Department of Pediatrics, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyDepartment of Pediatrics, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyDepartment of Infectious Diseases and Microbiology, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyMedical Systems Biology Group, Institute of Experimental Dermatology, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyDepartment of Pediatrics Pneumology & Allergology, University Medical Center Schleswig-Holstein, Lübeck, GermanyAirway Research Center North (ARCN) , Member of the German Center for Lung Research (DZL), Lübeck, GermanyDepartment of Pediatrics, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyCenter for Pediatric Research, Division of Neonatology, Department of Women’s and Children’s Health, University of Leipzig Medical Centre, Leipzig, GermanyCenter for Comprehensive Developmental Care (CDeCLMU), Member of the German Center for Lung Research (DZL), Hospital of the Ludwig-Maximilians University (LMU), CPC-M bioArchive, Munich, GermanyDepartment of Pediatrics, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyMedical Systems Biology Group, Institute of Experimental Dermatology, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyDepartment of Pediatrics, University of Lübeck and University Medical Center Schleswig-Holstein, Lübeck, GermanyDepartment of Pediatrics, University of Michigan, Ann Arbor, MI, United StatesDepartment of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, United States0Department of Pediatrics, University of Würzburg, Würzburg, GermanyPreterm 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.762789/fullpreterm infantssustained inflammationmacrophageshyperoxiahypoxiainfection |
| spellingShingle | Nele Twisselmann Julia Pagel Julia Pagel Axel Künstner Markus Weckmann Markus Weckmann Annika Hartz Kirsten Glaser Anne Hilgendorff Wolfgang Göpel Hauke Busch Egbert Herting Jason B. Weinberg Jason B. Weinberg Christoph Härtel Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation Frontiers in Immunology preterm infants sustained inflammation macrophages hyperoxia hypoxia infection |
| title | Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation |
| title_full | Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation |
| title_fullStr | Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation |
| title_full_unstemmed | Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation |
| title_short | Hyperoxia/Hypoxia Exposure Primes a Sustained Pro-Inflammatory Profile of Preterm Infant Macrophages Upon LPS Stimulation |
| title_sort | hyperoxia hypoxia exposure primes a sustained pro inflammatory profile of preterm infant macrophages upon lps stimulation |
| topic | preterm infants sustained inflammation macrophages hyperoxia hypoxia infection |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.762789/full |
| work_keys_str_mv | AT neletwisselmann hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT juliapagel hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT juliapagel hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT axelkunstner hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT markusweckmann hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT markusweckmann hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT annikahartz hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT kirstenglaser hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT annehilgendorff hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT wolfganggopel hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT haukebusch hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT egbertherting hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT jasonbweinberg hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT jasonbweinberg hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation AT christophhartel hyperoxiahypoxiaexposureprimesasustainedproinflammatoryprofileofpreterminfantmacrophagesuponlpsstimulation |