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  Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia

Hirani, D., Alvira, C. M., Danopoulos, S., Milla, C., Donato, M., Tian, L., et al. (2022). Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia. EUROPEAN RESPIRATORY JOURNAL, 59(2): 2002248. doi:10.1183/13993003.02248-2020.

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Hirani, Dharmesh, Author
Alvira, Cristina M., Author
Danopoulos, Soula, Author
Milla, Carlos, Author
Donato, Michele, Author
Tian, Lu, Author
Mohr, Jasmine, Author
Dinger, Katharina, Author
Vohlen, Christina, Author
Selle, Jaco, Author
Koningsbruggen-Rietschel V, Silke, Author
Barbarino, Verena, Author
Pallasch, Christian, Author
Rose-John, Stefan, Author
Odenthal, Margarete, Author
Pryhuber, Gloria S., Author
Mansouri, Siavash1, Author              
Savai, Rajkumar1, Author              
Seeger, Werner1, Author              
Khatri, Purvesh, Author
Al Alam, Denise, AuthorDoetsch, Joerg, AuthorAlcazar, Miguel A. Alejandre, Author more..
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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 Abstract: 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 Kruppel-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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 Dates: 2022-02-17
 Publication Status: Published online
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Title: EUROPEAN RESPIRATORY JOURNAL
Source Genre: Journal
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Pages: - Volume / Issue: 59 (2) Sequence Number: 2002248 Start / End Page: - Identifier: ISSN: 0903-1936