Hirani, Dharmesh, Alvira, Cristina M., Danopoulos, Soula, Milla, Carlos ORCID: 0000-0001-5515-3053, Donato, Michele, Tian, Lu, Mohr, Jasmine, Dinger, Katharina, Vohlen, Christina, Selle, Jaco ORCID: 0000-0002-4981-0931, Koningsbruggen-Rietschel, Silke, V, Barbarino, Verena, Pallasch, Christian, Rose-John, Stefan, Odenthal, Margarete, Pryhuber, Gloria S., Mansouri, Siavash, Savai, Rajkumar, Seeger, Werner ORCID: 0000-0003-1946-0894, Khatri, Purvesh ORCID: 0000-0002-4143-4708, Al Alam, Denise, Doetsch, Joerg and Alcazar, Miguel A. Alejandre (2022). Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia. Eur. Resp. J., 59 (2). SHEFFIELD: EUROPEAN RESPIRATORY SOC JOURNALS LTD. ISSN 1399-3003

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hirani, DharmeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alvira, Cristina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danopoulos, SoulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milla, CarlosUNSPECIFIEDorcid.org/0000-0001-5515-3053UNSPECIFIED
Donato, MicheleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tian, LuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohr, JasmineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dinger, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vohlen, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selle, JacoUNSPECIFIEDorcid.org/0000-0002-4981-0931UNSPECIFIED
Koningsbruggen-Rietschel, Silke, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barbarino, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rose-John, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pryhuber, Gloria S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mansouri, SiavashUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savai, RajkumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, WernerUNSPECIFIEDorcid.org/0000-0003-1946-0894UNSPECIFIED
Khatri, PurveshUNSPECIFIEDorcid.org/0000-0002-4143-4708UNSPECIFIED
Al Alam, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doetsch, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alcazar, Miguel A. AlejandreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-691254
DOI: 10.1183/13993003.02248-2020
Journal or Publication Title: Eur. Resp. J.
Volume: 59
Number: 2
Date: 2022
Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD
Place of Publication: SHEFFIELD
ISSN: 1399-3003
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ALVEOLAR EPITHELIAL-CELLS; ACUTE LUNG INJURY; INTERLEUKIN-6 RECEPTOR; MICE; INFLAMMATION; POLARIZATION; PROTECTION; FIBROSIS; THERAPY; INFANTSMultiple languages
Respiratory SystemMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69125

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