Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection
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
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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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 6

Repeated LPS exposures augment adaptive immune responses.

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Repeated LPS exposures augment adaptive immune responses. B6 recipient m...
B6 recipient mice received a single left lung transplant from B6 or B10 donor mice, followed by repeated intratracheal LPS versus PBS exposures. (A) Representative pictures of H&E staining on days 14 and 28 (Scale bar: 300 μm). Left: LPS syngraft. Middle: PBS allograft. Right: LPS allograft. Upper images are 14 days after lung transplantation. Bottom images are 28 days after lung transplantation. (B and C) Perivascular and periairway lymphocyte infiltration histological rejection scores of lung grafts on days 5, 14, 28, and 42 (n = 7–12 per group). Data are shown as mean ± SEM). (B) A-grade. (C) B-grade. Kruskal-Wallis test. LPS syngrafts versus LPS allografts, **P < 0.01; ***P < 0.001; ****P < 0.0001. PBS allografts versus LPS allografts, †P < 0.05. (D and E) CD4+ T cells and their subsets by lung cell flow cytometry on days 5, 14, and 28 (n = 3–4 per group). Data are shown as mean ± SEM). Data for each time point were obtained from different animals. (D) Total CD4+ T cells in lung grafts. (E) Effector memory CD4+ T cells (CD44+CD62L–CD4+ T cells, TEM) and CD44–CD62L–CD4+ T cells. Kruskal-Wallis test. LPS syngrafts versus LPS allografts, **P < 0.01.