A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair

D Karo-Atar; A Bordowitz; O Wand; M Pasmanik-Chor; I E Fernandez; M Itan; R Frenkel; D R Herbert; F D Finkelman; O Eickelberg; A Munitz

doi:10.1038/mi.2015.56

A protective role for IL-13 receptor α 1 in bleomycin-induced pulmonary injury and repair

Mucosal Immunol. 2016 Jan;9(1):240-53. doi: 10.1038/mi.2015.56. Epub 2015 Jul 8.

Authors

D Karo-Atar¹, A Bordowitz¹, O Wand¹, M Pasmanik-Chor², I E Fernandez³, M Itan¹, R Frenkel⁴, D R Herbert⁵, F D Finkelman^{6

7

8}, O Eickelberg³, A Munitz¹

Affiliations

¹ Department of Clinical Microbiology and Immunology, The Sackler School of Medicine, The Tel-Aviv University, Ramat Aviv, Israel.
² Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
³ Comprehensive Pneumology Center, Ludwig Maximilians University, University Hospital Grosshadern, and Helmholtz Zentrum München, Member of the German Center for Lung Research, Munich, Germany.
⁴ Department of Math, Physics and Computer Science, University of Cincinnati, Cincinnati, Ohio, USA.
⁵ Division of Experimental Medicine, University of California, San Francisco, California, USA.
⁶ Division of Allergy, Immunology and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁷ Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
⁸ Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Abstract

Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Animals
Bleomycin
Case-Control Studies
Female
Gene Expression Regulation
Homeostasis / immunology
Humans
Idiopathic Pulmonary Fibrosis / chemically induced
Idiopathic Pulmonary Fibrosis / genetics
Idiopathic Pulmonary Fibrosis / immunology*
Idiopathic Pulmonary Fibrosis / pathology
Interleukin-13 / genetics
Interleukin-13 / immunology*
Interleukin-13 Receptor alpha1 Subunit / deficiency
Interleukin-13 Receptor alpha1 Subunit / genetics
Interleukin-13 Receptor alpha1 Subunit / immunology*
Interleukin-17 / genetics
Interleukin-17 / immunology
Interleukin-4 / genetics
Interleukin-4 / immunology
Lung / immunology
Lung / pathology
Lung Injury / chemically induced
Lung Injury / genetics
Lung Injury / immunology*
Lung Injury / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Protein Isoforms / genetics
Protein Isoforms / immunology
Receptors, Interleukin-4 / genetics
Receptors, Interleukin-4 / immunology
Signal Transduction
Transcription, Genetic

Substances

Interleukin-13
Interleukin-13 Receptor alpha1 Subunit
Interleukin-17
Protein Isoforms
Receptors, Interleukin-4
Bleomycin
Interleukin-4

Grants and funding

R01 GM083204/GM/NIGMS NIH HHS/United States