Multi-Omics Integration Reveals Macrophage Lysosomal Remodeling as a Signature of Reparative Immunity in…

Abstract

Primary graft dysfunction (PGD) after lung transplantation is driven by ischemia-reperfusion injury (IRI), yet the early myeloid programs bridging inflammatory damage to reparative immunity remain incompletely defined. We integrated proteomic profiling of paired human lung allograft biopsies obtained after cold ischemia and early reperfusion (n = 8 pairs) with a public single-cell RNA-sequencing atlas, followed by functional validation in THP-1-derived macrophages. Reperfusion increased innate immune and extracellular matrix programs while decreasing lysosome- and phagosome-associated proteins. The downregulated signature mapped predominantly to macrophages and monocytes. Myeloid reclustering identified a transitional lipid-associated macrophage (LAM)/phagocytic state characterized by a prominent lysosome-associated transcriptional program. Cathepsin L (CTSL) emerged as a candidate lysosomal effector associated with this reparative state. Cellular origin analysis indicated this dynamic myeloid response involved both donor-resident macrophages and recipient-recruited monocytes. CTSL overexpression enhanced enzymatic activity, partially restored macrophage function, and dampened IRI-associated cytokine responses. These findings support a contributory role for CTSL in macrophage adaptation during early lung allograft reperfusion.

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BibTeX RIS

BibTeX

@article{li2026multiomics,
  title = {{Multi-Omics Integration Reveals Macrophage Lysosomal Remodeling as a Signature of Reparative Immunity in Human Lung Ischemia-Reperfusion Injury}},
  author = {Ming Li and Yixing Li and Hongyi Wang and Tianfei Wang and Zhe Chen and Rongxuan Jiang and Qiang Bai and Jinteng Feng and Guangjian Zhang},
  journal = {American Journal of Transplantation},
  year = {2026},
  month = sep,
  doi = {10.1016/j.ajt.2026.08.016},
  url = {https://hal.science/hal-05756444v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - Multi-Omics Integration Reveals Macrophage Lysosomal Remodeling as a Signature of Reparative Immunity in Human Lung Ischemia-Reperfusion Injury
AU  - Ming Li
AU  - Yixing Li
AU  - Hongyi Wang
AU  - Tianfei Wang
AU  - Zhe Chen
AU  - Rongxuan Jiang
AU  - Qiang Bai
AU  - Jinteng Feng
AU  - Guangjian Zhang
PY  - 2026
DA  - 2026/09/21
JO  - American Journal of Transplantation
DO  - 10.1016/j.ajt.2026.08.016
UR  - https://hal.science/hal-05756444v1
AB  - Primary graft dysfunction (PGD) after lung transplantation is driven by ischemia-reperfusion injury (IRI), yet the early myeloid programs bridging inflammatory damage to reparative immunity remain incompletely defined. We integrated proteomic profiling of paired human lung allograft biopsies obtained after cold ischemia and early reperfusion (n = 8 pairs) with a public single-cell RNA-sequencing atlas, followed by functional validation in THP-1-derived macrophages. Reperfusion increased innate immune and extracellular matrix programs while decreasing lysosome- and phagosome-associated proteins. The downregulated signature mapped predominantly to macrophages and monocytes. Myeloid reclustering identified a transitional lipid-associated macrophage (LAM)/phagocytic state characterized by a prominent lysosome-associated transcriptional program. Cathepsin L (CTSL) emerged as a candidate lysosomal effector associated with this reparative state. Cellular origin analysis indicated this dynamic myeloid response involved both donor-resident macrophages and recipient-recruited monocytes. CTSL overexpression enhanced enzymatic activity, partially restored macrophage function, and dampened IRI-associated cytokine responses. These findings support a contributory role for CTSL in macrophage adaptation during early lung allograft reperfusion.
SN  - 1600-6135
SN  - 1600-6143
ER  -

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