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Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection

AIMS: Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and i...

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Autores principales: Wu, Zhichao, Liang, Jialiang, Zhu, Shuoji, Liu, Nanbo, Zhao, Mingyi, Xiao, Fei, Li, Guanhua, Yu, Changjiang, Jin, Chengyu, Ma, Jinshan, Sun, Tucheng, Zhu, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535112/
https://www.ncbi.nlm.nih.gov/pubmed/37781362
http://dx.doi.org/10.3389/fimmu.2023.1251028
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author Wu, Zhichao
Liang, Jialiang
Zhu, Shuoji
Liu, Nanbo
Zhao, Mingyi
Xiao, Fei
Li, Guanhua
Yu, Changjiang
Jin, Chengyu
Ma, Jinshan
Sun, Tucheng
Zhu, Ping
author_facet Wu, Zhichao
Liang, Jialiang
Zhu, Shuoji
Liu, Nanbo
Zhao, Mingyi
Xiao, Fei
Li, Guanhua
Yu, Changjiang
Jin, Chengyu
Ma, Jinshan
Sun, Tucheng
Zhu, Ping
author_sort Wu, Zhichao
collection PubMed
description AIMS: Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. METHODS: A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. RESULTS: A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. CONCLUSION: The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.
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spelling pubmed-105351122023-09-29 Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection Wu, Zhichao Liang, Jialiang Zhu, Shuoji Liu, Nanbo Zhao, Mingyi Xiao, Fei Li, Guanhua Yu, Changjiang Jin, Chengyu Ma, Jinshan Sun, Tucheng Zhu, Ping Front Immunol Immunology AIMS: Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. METHODS: A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. RESULTS: A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. CONCLUSION: The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection. Frontiers Media S.A. 2023-09-13 /pmc/articles/PMC10535112/ /pubmed/37781362 http://dx.doi.org/10.3389/fimmu.2023.1251028 Text en Copyright © 2023 Wu, Liang, Zhu, Liu, Zhao, Xiao, Li, Yu, Jin, Ma, Sun and Zhu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wu, Zhichao
Liang, Jialiang
Zhu, Shuoji
Liu, Nanbo
Zhao, Mingyi
Xiao, Fei
Li, Guanhua
Yu, Changjiang
Jin, Chengyu
Ma, Jinshan
Sun, Tucheng
Zhu, Ping
Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title_full Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title_fullStr Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title_full_unstemmed Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title_short Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
title_sort single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535112/
https://www.ncbi.nlm.nih.gov/pubmed/37781362
http://dx.doi.org/10.3389/fimmu.2023.1251028
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