Dysregulation of innate cell types in the hepatic immune microenvironment of alcoholic liver cirrhosis

Ao Ren; Wenjing He; Jiawei Rao; Dongmei Ye; Pengrui Cheng; Qian Jian; Zongli Fu; Xuzhi Zhang; Ronghai Deng; Yifang Gao; Yi Ma

doi:10.3389/fimmu.2023.1034356

Dysregulation of innate cell types in the hepatic immune microenvironment of alcoholic liver cirrhosis

Front Immunol. 2023 Feb 9:14:1034356. doi: 10.3389/fimmu.2023.1034356. eCollection 2023.

Authors

Ao Ren^{1

2

3}, Wenjing He^{1

2

3}, Jiawei Rao^{1

2

3}, Dongmei Ye^{1

2

3}, Pengrui Cheng^{1

2

3}, Qian Jian^{1

2

3}, Zongli Fu^{1

2

3}, Xuzhi Zhang^{1

2

3}, Ronghai Deng^{1

2

3}, Yifang Gao^{1

2

3}, Yi Ma^{1

2

3}

Affiliations

¹ Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Abstract

Introduction: The risk of alcoholic cirrhosis increases in a dose- and time-dependent manner with alcohol consumption and ethanol metabolism in the liver. Currently, no effective antifibrotic therapies are available. We aimed to obtain a better understanding of the cellular and molecular mechanisms involved in the pathogenesis of liver cirrhosis.

Methods: We performed single-cell RNA-sequencing to analyze immune cells from the liver tissue and peripheral blood form patients with alcoholic cirrhosis and healthy controls to profile the transcriptomes of more than 100,000 single human cells and yield molecular definitions for non-parenchymal cell types. In addition, we performed single-cell RNA-sequencing analysis to reveal the immune microenvironment related to alcoholic liver cirrhosis. Hematoxylin and eosin, Immunofluorescence staining and Flow cytometric analysis were employed to study the difference between tissues and cells with or without alcoholic cirrhosis.

Results: We identified a fibrosis-associated M1 subpopulation of macrophages that expands in liver fibrosis, differentiates from circulating monocytes, and is pro-fibrogenic. We also define mucosal-associated invariant T (MAIT) cells that expand in alcoholic cirrhosis and are topographically restricted to the fibrotic niche. Multilineage modeling of ligand and receptor interactions between the fibrosis-associated macrophages, MAIT, and NK cells revealed the intra-fibrotic activity of several pro-fibrogenic pathways, including responses to cytokines and antigen processing and presentation, natural killer cell-mediated cytotoxicity, cell adhesion molecules, Th1/Th2/Th17 cell differentiation, IL-17 signaling pathway, and Toll-like receptor signaling pathway.

Discussion: Our work dissects unanticipated aspects of the cellular and molecular basis of human organ alcoholic fibrosis at the single-cell level and provides a conceptual framework for the discovery of rational therapeutic targets in liver alcoholic cirrhosis.

Keywords: MAIT cells; NKT cells; fibrosis; macrophages; scRNA-seq.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytokines
Humans
Liver Cirrhosis*
Liver Cirrhosis, Alcoholic* / pathology
Macrophages

Substances

Cytokines

Grants and funding

This research was supported by grants from Natural Science Foundation of Guangdong Province, China (2022A1515011052), National Natural Science Foundation of China, China (81873591), The Science and Technology Planning Project of Guangdong Province, China (2018A050506030). The Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2020B1212060026 and 2017B030314018), Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation) (2015B050501002).