Background
Lung transplant recipients experience episodes of immune-mediated acute lung allograft
dysfunction (ALAD). ALAD episodes are a risk factor for chronic lung allograft dysfunction
(CLAD), the major cause of death after lung transplantation.
Our objective was to determine key cellular elements in dysfunctional lung allografts,
with a focus on macrophages.
Methods
We have applied single-cell RNA sequencing (scRNAseq) to bronchoalveolar lavage cells
from stable and ALAD patients and to cells from explanted CLAD lung tissue.
Results
We identified 2 alveolar macrophage (AM) subsets uniquely represented in ALAD. Using
pathway analysis and differentially expressed genes, we annotated these as pro-inflammatory
interferon-stimulated gene (ISG) and metallothionein-mediated inflammatory (MT) AMs.
Functional analysis of an independent set of AMs in vitro revealed that ALAD AMs exhibited
a higher expression of CXCL10, a marker of ISG AMs, and increased secretion of pro-inflammatory
cytokines compared to AMs from stable patients. Using publicly available bronchoalveolar
lavage scRNAseq datasets, we found that ISG and MT AMs are associated with more severe
inflammation in COVID-19 patients. Analysis of cells from 4 explanted CLAD lungs revealed
similar macrophage populations. Donor and recipient cells were identified using expressed
single nucleotide variations. We demonstrated contributions of donor and recipient
cells to all AM subsets early post-transplant, with loss of donor-derived cells over
time.
Conclusions
Our data reveal extensive heterogeneity among lung macrophages after lung transplantation
and indicates that specific sub-populations may be associated with allograft dysfunction,
raising the possibility that these cells may represent important therapeutic targets.
KEYWORDS
Abbreviations:
ALAD (acute lung allograft dysfunction), AM (alveolar macrophage), BAL (Bronchoalveolar lavage), CLAD (chronic lung allograft dysfunction), ISG (interferon-stimulated gene), MT (metallothionein), scRNAseq (single-cell RNA sequencing)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: May 19, 2022
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© 2022 International Society for Heart and Lung Transplantation. All rights reserved.
