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Scientific article
English

Interferon-stimulated and metallothionein-expressing macrophages are associated with acute and chronic allograft dysfunction after lung transplantation

Published inThe journal of heart and lung transplantation, vol. 41, no. 11, p. 1556-1569
Publication date2022-11
First online date2022-05-20
Abstract

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.

eng
Keywords
  • Acute lung allograft dysfunction
  • Alveolar macrophage
  • Chronic lung allograft dysfunction
  • Lung transplant
  • Single cell RNA sequencing
  • Humans
  • Interferons
  • Metallothionein / genetics
  • Graft Rejection
  • Bronchoalveolar Lavage Fluid
  • COVID-19
  • Lung Transplantation / adverse effects
  • Lung
  • Macrophages, Alveolar
  • Allografts
Affiliation Not a UNIGE publication
Citation (ISO format)
MOSHKELGOSHA, Sajad et al. Interferon-stimulated and metallothionein-expressing macrophages are associated with acute and chronic allograft dysfunction after lung transplantation. In: The journal of heart and lung transplantation, 2022, vol. 41, n° 11, p. 1556–1569. doi: 10.1016/j.healun.2022.05.005
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ISSN of the journal1053-2498
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