PMID- 37228276
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230528
IS  - 2312-0541 (Print)
IS  - 2312-0541 (Electronic)
IS  - 2312-0541 (Linking)
VI  - 9
IP  - 3
DP  - 2023 May
TI  - Interleukin-11 disrupts alveolar epithelial progenitor function.
LID - 00679-2022 [pii]
LID - 10.1183/23120541.00679-2022 [doi]
AB  - BACKGROUND: Interleukin-11 (IL-11) is linked to the pathogenesis of idiopathic 
      pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and 
      stimulates their excessive collagen deposition in the lung. In IPF there is 
      disrupted alveolar structural architecture, yet the effect of IL-11 on the 
      dysregulated alveolar repair remains to be elucidated. METHODS: We hypothesised 
      that epithelial-fibroblast communication associated with lung repair is disrupted 
      by IL-11. Thus, we studied whether IL-11 affects the repair responses of alveolar 
      lung epithelium using mouse lung organoids and precision-cut lung slices (PCLS). 
      Additionally, we assessed the anatomical distribution of IL-11 and IL-11 receptor 
      (IL-11R) in human control and IPF lungs using immunohistochemistry. RESULTS: 
      IL-11 protein was observed in airway epithelium, macrophages and in IPF lungs, 
      also in areas of alveolar type 2 (AT2) cell hyperplasia. IL-11R staining was 
      predominantly present in smooth muscle and macrophages. In mouse organoid 
      co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid 
      number and reduced the fraction of Prosurfactant Protein C-expressing organoids, 
      indicating dysfunctional regeneration initiated by epithelial progenitors. In 
      mouse PCLS exposed to IL-11, ciliated cell markers were increased. The response 
      of primary human fibroblasts to IL-11 on gene expression level was minimal, 
      though bulk RNA-sequencing revealed IL-11 modulated various processes which are 
      associated with IPF, including unfolded protein response, glycolysis and Notch 
      signalling. CONCLUSIONS: IL-11 disrupts alveolar epithelial regeneration by 
      inhibiting progenitor activation and suppressing the formation of mature alveolar 
      epithelial cells. Evidence for a contribution of dysregulated 
      fibroblast-epithelial communication to this process is limited.
CI  - Copyright (c)The authors 2023.
FAU - Kortekaas, Rosa K
AU  - Kortekaas RK
AUID- ORCID: 0000-0002-8728-1735
AD  - Department of Molecular Pharmacology, University of Groningen, Groningen, the 
      Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD, Groningen, the Netherlands.
FAU - Geillinger-Kastle, Kerstin E
AU  - Geillinger-Kastle KE
AD  - Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim 
      Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Borghuis, Theo
AU  - Borghuis T
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Pathology and Medical Biology, Groningen, the Netherlands.
FAU - Belharch, Kaoutar
AU  - Belharch K
AD  - Department of Molecular Pharmacology, University of Groningen, Groningen, the 
      Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD, Groningen, the Netherlands.
FAU - Webster, Megan
AU  - Webster M
AD  - Department of Immunology and Respiratory Diseases Research, Boehringer Ingelheim 
      Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
FAU - Timens, Wim
AU  - Timens W
AUID- ORCID: 0000-0002-4146-6363
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD, Groningen, the Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Pathology and Medical Biology, Groningen, the Netherlands.
FAU - Burgess, Janette K
AU  - Burgess JK
AUID- ORCID: 0000-0001-9868-9966
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD, Groningen, the Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Pathology and Medical Biology, Groningen, the Netherlands.
AD  - These authors contributed equally.
FAU - Gosens, Reinoud
AU  - Gosens R
AD  - Department of Molecular Pharmacology, University of Groningen, Groningen, the 
      Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Groningen Research 
      Institute for Asthma and COPD, Groningen, the Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Pathology and Medical Biology, Groningen, the Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20230522
PL  - England
TA  - ERJ Open Res
JT  - ERJ open research
JID - 101671641
PMC - PMC10204861
COIS- Conflict of interest: R.K. Kortekaas declares funding for the present manuscript 
      from Boehringer Ingelheim (unrestricted research funds to their institute) and an 
      internship contract with Boehringer Ingelheim in the 36 months prior to 
      manuscript submission. K.E. Geillinger-Kastle is an employee of Boehringer 
      Ingelheim. M. Webster is a former employee of Boehringer Ingelheim and a current 
      employee of Newcells Biotech. W. Timens declares consulting fees from Merck Sharp 
      & Dohme and Bristol Myers Squibb in the 36 months prior to manuscript submission; 
      and that they are a board member of the Dutch Society of Pathology, and a member 
      of the Council for Research and Innovation of the Federation of Medical 
      Specialists. J.K. Burgess declares funding for the present manuscript from 
      Boehringer Ingelheim (unrestricted research funds to their institute) and 
      Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Aspasia-premie 
      subsidienummer 015.013.010, paid to their institute). R. Gosens declares funding 
      for the present manuscript from Boehringer Ingelheim (paid to their institute); 
      as well as grants paid to their institution from Aquilo and Sanofi-Genzyme in the 
      36 months prior to manuscript submission. All other authors declare no competing 
      interests.
EDAT- 2023/05/25 19:12
MHDA- 2023/05/25 19:13
PMCR- 2023/05/22
CRDT- 2023/05/25 14:04
PHST- 2022/12/06 00:00 [received]
PHST- 2023/03/08 00:00 [accepted]
PHST- 2023/05/25 19:13 [medline]
PHST- 2023/05/25 19:12 [pubmed]
PHST- 2023/05/25 14:04 [entrez]
PHST- 2023/05/22 00:00 [pmc-release]
AID - 00679-2022 [pii]
AID - 10.1183/23120541.00679-2022 [doi]
PST - epublish
SO  - ERJ Open Res. 2023 May 22;9(3):00679-2022. doi: 10.1183/23120541.00679-2022. 
      eCollection 2023 May.