Klin Padiatr 2025; 237(02): S15
DOI: 10.1055/s-0045-1802510
Abstracts
Experimentelle Pneumologie

Obesity related IL-6 trans-signaling is linked to BMI in pediatric asthma and associated with premature aging of respiratory epithelial cells in mice and children

T Trojan
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
2   University of Cologne, University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine, Excellence Cluster on Stress Responses in Aging-associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), Köln, North Rhine-Westphalia, Germany
,
L Riemann
6   Hannover Medical School, Department of pediatric Pneumology, Allergology and Neonatology, Hannover, Lower Saxony, Germany
7   Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Lower Saxony, Germany
,
S Buchholz
3   Airway Research Center North (ARCN), Germany
8   Division of Pediatric Pneumology and Allergology, University Children's Hospital Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Schleswig-Holstein, Germany
,
K D Reddy
3   Airway Research Center North (ARCN), Germany
8   Division of Pediatric Pneumology and Allergology, University Children's Hospital Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Schleswig-Holstein, Germany
12   Division of Epigenetics in Chronic Lung Disease, Priority Area Chronic Lung Diseases, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
,
C Thomassen
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
,
S Blau
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
,
J Selle
2   University of Cologne, University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine, Excellence Cluster on Stress Responses in Aging-associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), Köln, North Rhine-Westphalia, Germany
,
M V Kopp
4   University of Bern, Inselspital, Department of Pediatrics, Bern, Bern, Switzerland
,
M Abdo
5   LungenClinic Grosshansdorf GmbH, Grosshansdorf, Schleswig-Holstein, Germany
,
A M Dittrich
6   Hannover Medical School, Department of pediatric Pneumology, Allergology and Neonatology, Hannover, Lower Saxony, Germany
7   Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Lower Saxony, Germany
,
R Grychtol
6   Hannover Medical School, Department of pediatric Pneumology, Allergology and Neonatology, Hannover, Lower Saxony, Germany
7   Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Lower Saxony, Germany
,
F Brinkmann
3   Airway Research Center North (ARCN), Germany
8   Division of Pediatric Pneumology and Allergology, University Children's Hospital Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Schleswig-Holstein, Germany
,
G Hansen
6   Hannover Medical School, Department of pediatric Pneumology, Allergology and Neonatology, Hannover, Lower Saxony, Germany
7   Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Lower Saxony, Germany
,
B Schaub
9   Ludwig Maximilians University, Dr. von Hauner Children's Hospital, München, Bavaria, Germany
10   Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), München, Bavaria, Germany
11   German Center for Child and Adolescent Health (DZKJ), Dr von Hauner Children's Hospital, LMU Munich, Germany
,
E von Mutius
9   Ludwig Maximilians University, Dr. von Hauner Children's Hospital, München, Bavaria, Germany
10   Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), München, Bavaria, Germany
,
E Rietschel
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
,
S van Koningsbruggen-Rietschel
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
,
M Weckmann
3   Airway Research Center North (ARCN), Germany
8   Division of Pediatric Pneumology and Allergology, University Children's Hospital Lübeck, University Medical Center Schleswig-Holstein, Lübeck, Schleswig-Holstein, Germany
12   Division of Epigenetics in Chronic Lung Disease, Priority Area Chronic Lung Diseases, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
,
C Happle
6   Hannover Medical School, Department of pediatric Pneumology, Allergology and Neonatology, Hannover, Lower Saxony, Germany
7   Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Lower Saxony, Germany
,
M Alejandre Alcazar
1   University of Cologne, University Hospital Cologne, Department of Pediatrics and Adolescent Medicine, Department of Pediatric Pulmonology and Allergology, Köln, North Rhine-Westphalia, Germany
2   University of Cologne, University Hospital Cologne, Translational Experimental Pediatrics, Department of Pediatric and Adolescent Medicine, Excellence Cluster on Stress Responses in Aging-associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), Köln, North Rhine-Westphalia, Germany
13   Institute for Lung Health (ILH) and Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Centre (UGMLC), Member of the German Centre for Lung Research (DZL), Giessen, Hesse, Germany
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Background: Obesity early in life affects the clinical course of asthma. Maternal obesity is a risk factor for childhood obesity, but the impact on asthma phenotypes is unclear. Our previously reported findings in the All-Age Asthma Cohort (ALLIANCE) study showed a clinical association between (a) maternal BMI and asthma severity in the offspring, (b) high body-mass-index (BMI) and high bodyfat-fraction (BFF) in early life and a worse symptom control of asthma, earlier onset of symptoms and lower lung function. Additionally, (c) methylome profiling with methylome-derived epigenetic clock in nasal respiratory epithelial cells (REC) of asthmatic children showed premature epithelial cell aging in overweight asthmatics. Therefore, we now investigated obesity-related inflammation, including the pathways of adipocytokine Interleukin-6 (IL-6) in (i) the ALLIANCE cohort and (ii) a murine model of perinatal obesity with pharmacological IL-6 intervention.

Methods: (i) In 324 study participants (asthmatics and controls, mean age: 9,6 years [SD: 4.0], 123 females [38%], 201 males [62%]) we conducted a cytokine cluster analysis in CD3/CD28 stimulated whole blood of asthmatic children to test for association with clinical parameters. Furthermore, in 139 patients and controls we investigated IL-6 related analytes for possible correlation with BMI and GINA symptom control in the asthmatics. (ii) In a murine perinatal obesity model, we analyzed aging-associated processes (e.g., DNA damage) in bronchial epithelial cells (BEC) via immunofluorescent staining with yH2AX after postnatal pharmacological inhibition of IL-6 cis- and trans- signaling using mIL-6Ab or sgp130Fc, respectively.

Results: On a molecular level, assessment of cytokine modules in CD3/CD28 stimulated whole blood of asthmatic children identified a cytokine cluster that correlated with high BMI (p<0,001) and lower lung function trajectory (p<0,01) in asthmatics. On a clinical level, lower levels of soluble gp130 (sgp130), a natural inhibitor of IL-6 trans-signaling, were associated with high BMI (p<0,001) and lower symptom control (p<0,01). (ii) In the murine model, perinatal obesity was linked to increased signs of aging (i.e. higher DNA damage response) in BECs, which was protected against when IL-6 trans-signaling was inhibited with sgp130Fc (p<0,01).

Conclusion: Our results highlight the impact of obesity-associated meta-inflammation, specifically the role of IL6 trans-signaling, on lower symptom control as an indicator of asthma severity in childhood. Obesity-driven premature aging of respiratory epithelial cells could be a pathomechanism for epithelial dysfunction and targeting IL-6 trans-signaling could be a novel therapeutic strategy for patients with obesity-related asthma.



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Artikel online veröffentlicht:
28. Februar 2025

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