Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia
Dharmesh Hirani1,2, Cristina M Alvira3, Soula Danopoulos4
1University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics - Experimental Pulmonology, Dept of Pediatric and Adolescent Medicine, Cologne, Germany.
Insights
Oxygen exposure in premature infants can cause bronchopulmonary dysplasia (BPD), halting lung growth. This study reveals that targeting interleukin-6 (IL-6) signaling in macrophages may protect lung development and function in BPD.
Area of Science:
- Neonatal Medicine
- Pulmonary Biology
- Immunology
Background:
- Premature infants receiving oxygen therapy are at risk for bronchopulmonary dysplasia (BPD), a condition characterized by impaired lung growth.
- The precise inflammatory mechanisms driving BPD pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the inflammatory pathways involved in hyperoxia-induced lung injury and identify potential therapeutic targets for BPD.
Main Methods:
- Transcriptomic analysis and in silico deconvolution in hyperoxia-exposed newborn mice.
- In vivo measurement of IL-6/STAT3 signaling and its impact on alveolar epithelial type II cells (ATII).
- Assessment of macrophage polarization and function in response to hyperoxia and IL-6.
Main Results:
- Hyperoxia induced an M1-like macrophage-driven cytokine pattern, characterized by elevated IL-6 and STAT3 signaling.
- IL-6 signaling disruption preserved ATII cell survival, improved elastic fiber assembly, and promoted lung growth in mice.
- Macrophage-derived IL-6 and STAT3 activation correlated with epithelial cell loss in human BPD lungs, with elevated plasma cytokines serving as potential biomarkers.
Conclusions:
- A novel IL-6-mediated mechanism involving macrophage activation, ATII cell dysfunction, and disrupted elastic fiber formation inhibits lung growth in hyperoxia-exposed immature lungs.
- Targeting IL-6 trans-signalling presents a promising therapeutic strategy to promote lung growth in severe neonatal chronic lung disease.
Rationale:
Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.
Methods And Results:
First, transcriptomic analysis with in silico cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (Ccl2, Ccl7, Cxcl5) and markers (Il6, Il17A, Mmp12). Secondly, hyperoxia-activated interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signalling was measured in vivo and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. Il6 null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fibre assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signalling and IL-6 trans-signalling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly via Krüppel-like factor 4; hyperoxia-conditioned medium of macrophages and IL-6-impaired ATII proliferation. Finally, clinical data demonstrated elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived IL6 and active STAT3 were related to loss of epithelial cells in BPD lungs.
Conclusion:
We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis and disrupts elastic fibre formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signalling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.
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