Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection
Tatsuaki Watanabe, … , Shaf Keshavjee, Tereza Martinu
Tatsuaki Watanabe, … , Shaf Keshavjee, Tereza Martinu
Published November 8, 2023
Citation Information: JCI Insight. 2023;8(21):e158002. https://doi.org/10.1172/jci.insight.158002.
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Research Article Pulmonology Transplantation

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

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.

Authors

Tatsuaki Watanabe, Stephen C. Juvet, Gregory Berra, Jan Havlin, Wenshan Zhong, Kristen Boonstra, Tina Daigneault, Miho Horie, Chihiro Konoeda, Grace Teskey, Zehong Guan, David M. Hwang, Mingyao Liu, Shaf Keshavjee, Tereza Martinu

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Figure 1

CLAD lungs with antecedent infectious episodes.

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CLAD lungs with antecedent infectious episodes. Human CLAD allografts fr...
Human CLAD allografts from patients with repeated pulmonary infection episodes after transplant. (A–F) Trajectories of forced expiratory volume in 1 second (FEV1) over time, of lung transplant recipients with recurrent episodes of pulmonary infections followed by CLAD development. Black arrows indicate gram-negative bacterial infection. White arrows indicate infection with bacteria other than gram-negative bacteria. A blue arrowhead indicates the onset of CLAD. A red arrowhead indicates retransplantation. Acute rejection A-grades, based on transbronchial biopsies, are indicated above the graphs. (A) Case 1 in Supplemental Table 1. (B) Case 2 in Supplemental Table 1. (C) Case 3 in Supplemental Table 1. (D) Case 4 in Supplemental Table 1. (E) Case 5 in Supplemental Table 1. (F) Case 6 in Supplemental Table 1. (G) Representative images of airway pathology from explanted CLAD lungs compared with a human donor lung as control. Left: Donor lung sample obtained at volume reduction during transplantation showed normal airway epithelium. Middle: Explanted CLAD lung (Case A) showed airway epithelial hyperplasia. Right: Explanted CLAD lungs (Case F) showed airway epithelial destruction and epithelial flattening. Scale bar: 200 μm. ET, Elastic Trichrome.