Monocyte signature as a predictor of chronic lung disease in the preterm infant

Frontiers in Immunology

Immunology

Christoph Hübener¹  Andreas W. Flemmer²  Kai Förster³  Harald Ehrhardt⁴  Christian Schulz⁵  Erika Gonzalez Rodriguez⁶  Tobias Stoeger⁶  Motaharehsadat Heydarian⁶  Marion Frankenberger⁶  Xin Zhang⁶  Prajakta Oak⁶  Anne Hilgendorff⁷  Maren Schwarz⁸  Hamid Hossain⁹  Anita C. Windhorst^1,10 

[1] Department of Gynecology and Obstetrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilian-University, Munich, Germany;Department of Neonatology, Dr. von Hauner Childre's Hospital, University Hospital, Ludwig-Maximilian-University, Munich, Germany;Department of Neonatology, Dr. von Hauner Childre's Hospital, University Hospital, Ludwig-Maximilian-University, Munich, Germany;Center for Comprehensive Developmental Care (CDeCLMU) at the Social Pediatric Center, Dr. von Hauner Children`s Hospital, Ludwig Maximilian University (LMU) Hospital, Ludwig-Maximilian-University, Munich, Germany;Division of Neonatology and Pediatric Intensive Care Medicine, University Medical Center Ulm, Ulm, Germany;Department of General Pediatrics and Neonatology, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany;German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany;Department of Medicine I, University Hospital, Ludwig Maximilian University, Munich, Germany;Institute for Lung Health and Immunity and Comprehensive Pneumology Center, Helmholtz Zentrum München, German Center for Lung Research (DZL), Munich, Germany;Institute for Lung Health and Immunity and Comprehensive Pneumology Center, Helmholtz Zentrum München, German Center for Lung Research (DZL), Munich, Germany;Center for Comprehensive Developmental Care (CDeCLMU) at the Social Pediatric Center, Dr. von Hauner Children`s Hospital, Ludwig Maximilian University (LMU) Hospital, Ludwig-Maximilian-University, Munich, Germany;Institute for Lung Health and Immunity and Comprehensive Pneumology Center, Helmholtz Zentrum München, German Center for Lung Research (DZL), Munich, Germany;Department of Neonatology, Dr. von Hauner Childre's Hospital, University Hospital, Ludwig-Maximilian-University, Munich, Germany;Institute for Medical Microbiology, Justus-Liebig-University Giessen, Giessen, Germany;Institute of Medical Informatics, Justus-Liebig-University Giessen, Giessen, Germany;

关键词: bronchopulmonary dysplasia;    monocytes;    cytokines;    preterm infants;    prenatal injury;    chronic lung disease;   

DOI  :  10.3389/fimmu.2023.1112608

 received in 2022-11-30, accepted in 2023-03-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionInflammation is a key driver of morbidity in the vulnerable preterm infant exposed to pre- and postnatal hazards and significantly contributes to chronic lung disease, i.e. bronchopulmonary dysplasia (BPD). However, the early changes in innate immunity associated with BPD development are incompletely understood.MethodsIn very immature preterm infants below 32 weeks gestational age (GA; n=30 infants), monocyte subtypes were identified by Flow Cytometry at birth and throughout the postnatal course including intracellular TNF expression upon LPS stimulation. Complementing these measurements, cytokine end growth factor expression profiles (Luminex® xMAP®; n=110 infants) as well as gene expression profiles (CodeLinkTM Human I Bioarray; n=22) were characterized at birth.ResultsThe abundance of monocyte subtypes differed between preterm and term neonates at birth. Specifically, CD14++CD16+ (intermediate) monocytes demonstrated a dependency on PMA and elevated levels of nonclassical (CD14+CD16++) monocytes characterized preterm infants with developing BPD. Postnatally, lung injury was associated with an increase in intermediate monocytes, while high levels of nonclassical monocytes persisted. Both subtypes were revealed as the main source of intracellular TNF-α expression in the preterm infant. We identified a cytokine and growth factor expression profile in cord blood specimen of preterm infants with developing BPD that corresponded to the disease-dependent regulation of monocyte abundances. Multivariate modeling of protein profiles revealed FGF2, sIL-2 Rα, MCP-1, MIP1a, and TNF-α as predictors of BPD when considering GA. Transcriptome analysis demonstrated genes predicting BPD to be overrepresented in inflammatory pathways with increased disease severity characterized by the regulation of immune and defense response pathways and upstream regulator analysis confirmed TNF-α, interleukin (IL) -6, and interferon α as the highest activated cytokines in more severe disease. Whereas all BPD cases showed downstream activation of chemotaxis and activation of inflammatory response pathways, more severe cases were characterized by an additional activation of reactive oxygen species (ROS) synthesis.DiscussionIn the present study, we identified the early postnatal presence of nonclassical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes as a critical characteristic of BPD development including a specific response pattern of monocyte subtypes to lung injury. Pathophysiological insight was provided by the protein and transcriptome signature identified at birth, centered around monocyte and corresponding granulocyte activation and highlighting TNFα as a critical regulator in infants with developing BPD. The disease severity-dependent expression patterns could inform future diagnostic and treatment strategies targeting the monocytic cell and its progeny.

【 授权许可】

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Copyright © 2023 Windhorst, Heydarian, Schwarz, Oak, Förster, Frankenberger, Gonzalez Rodriguez, Zhang, Ehrhardt, Hübener, Flemmer, Hossain, Stoeger, Schulz and Hilgendorff