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Scientific article
Open access
English

Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Published inJCI insight, vol. 8, no. 21, e158002
Publication date2023-11-08
First online date2023-11-08
Abstract

Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.

eng
Keywords
  • Adaptive immunity
  • Fibrosis
  • Innate immunity
  • Pulmonology
  • Transplantation
  • Mice
  • Humans
  • Animals
  • Interleukin-17 / metabolism
  • Receptors, Interleukin-17 / metabolism
  • Lipopolysaccharides / toxicity
  • Lipopolysaccharides / metabolism
  • Pulmonary Fibrosis / pathology
  • Lung / pathology
  • Inflammation / metabolism
  • Respiratory Tract Infections / metabolism
  • Allografts
Affiliation Not a UNIGE publication
Citation (ISO format)
WATANABE, Tatsuaki et al. Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection. In: JCI insight, 2023, vol. 8, n° 21, p. e158002. doi: 10.1172/jci.insight.158002
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Article (Published version)
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ISSN of the journal2379-3708
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