Highlights
- •Translated in vitro human stromal-myeloid interactions to cells in human cirrhosis.
- •Stromal cells limit the transition of CD14+ monocytes into HLA-DRhi macrophages.
- •Stromal cell-secreted IL-6 limits the macrophage differentiation into CD9+ cirrhotic macrophages.
- •Local IL-6 levels are decreased in early-stage human liver disease.
Background & Aims
Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide.
Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic
strategy. We aimed to investigate how human liver stromal cells impact myeloid cell
properties and to understand the utility of a stromal-myeloid coculture system to
study these interactions in the context of cirrhosis.
Methods
Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5)
human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric
analysis were performed on human liver stromal-myeloid coculture systems.
Results
We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal
cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced
in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which
stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage
human liver disease compared to healthy liver tissue, suggesting a protective role
for local IL-6 in the healthy liver.
Conclusions
Our work reveals an unanticipated role for liver stromal cells in impeding the maturation
and altering the differentiation of macrophages and should prompt investigations into
the role of local IL-6 production in the pathogenesis of liver disease. These studies
provide a framework for investigating macrophage-stromal interactions during cirrhosis.
Lay summary
The impact of human liver stromal cells on myeloid cell maturation and differentiation
in liver disease is incompletely understood. In this study, we present a mechanistic
analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease
using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver
tissue. Our work supports a role for stromal cell contact in restricting macrophage
maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic
macrophage subset.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Burden of liver diseases in the world.J Hepatol. 2019; 70: 151-171
- Immunopathobiology and therapeutic targets related to cytokines in liver diseases.Cell Mol Immunol. 2020; : 1-20
- Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.J Hepatol. 2014; 61: 1385-1396
- The innate immune cells in cirrhosis.J Hepatol. 2020; 73: 186-201
- Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J Clin Invest. 2005; 115: 56-65
- Resolving the fibrotic niche of human liver cirrhosis at single cell level.Nature. 2019; 575: 512-518
- A human liver cell atlas reveals heterogeneity and epithelial progenitors.Nature. 2019; 572: 199-204
- Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.Nat Commun. 2018; 9 (2018)
- The role of myeloid-derived cells in the progression of liver disease.Front Immunol. 2019; 10
- Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge.J Hepatol. 1995; 22: 226-229
- Regulation of macrophage development and function in peripheral tissues.Nat Rev Immunol. 2015; 15: 731-744
- Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche.Immunity. 2019; 51: 638-654.e9
- Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion.J Hepatol. 2013; 59: 528-535
- Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal.Nat Immunol. 2020; 21: 555-566
- Joint analysis of heterogeneous single-cell RNA-seq dataset collections.Nat Method. 2019; 16: 695-698
- Accurate estimation of cell-type composition from gene expression data.Nat Commun. 2019; 10: 2975
- Landscape and dynamics of single immune cells in hepatocellular carcinoma.Cell. 2019; 179: 829-845
- Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma.Cell Res. 2019; 29: 725-738
- IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6.Int J Biol Sci. 2012; 8: 1237-1247
- Plasma interleukin-6 levels in patients with cirrhosis. Relationship to endotoxemia, tumor necrosis factor-alpha, and hyperdynamic circulation.Scand J Gastroenterol. 1996; 31: 500-505
- Diagnostic and prognostic role of serum interleukin-6 in malignant transformation of liver cirrhosis.Euroasian J Hepato-Gastroenterol. 2018; 8: 23-30
- Increased level of interleukin 6 associates with increased 90-day and 1-year mortality in patients with end-stage liver disease.Clin Gastroenterol Hepatol. 2018; 16: 730-737
- Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids.Hepatology. 2015; 61: 1565-1578
- Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017.The Lancet. 2018; 392: 1736-1788
Article info
Publication history
Published online: January 20, 2022
Accepted:
December 17,
2021
Received in revised form:
December 1,
2021
Received:
April 26,
2021
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
