The Role of Myeloid-Derived Cells in the Progression of Liver Disease

Weston, Chris J.; Zimmermann, Henning W.; Adams, David H.

doi:10.3389/fimmu.2019.00893

Cited by 79 publications

(89 citation statements)

References 257 publications

(284 reference statements)

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“…Identification of an apparently protective CD68+CD14+ cell population (Fig. ) is similar to other studies of tolerogenic livers and a recent study of human intrahepatic macrophages that analyzed populations using single‐cell RNA sequencing, where they had immunoregulatory and patrolling type functions . Three main macrophage clusters were significantly increased in patients who were HCV‐positive with advanced fibrosis when compared to controls, and included CD163+CD16+, CD68+, and CD68+MAC387+.…”

Section: Discussionsupporting

confidence: 81%

Multispectral Imaging Enables Characterization of Intrahepatic Macrophages in Patients With Chronic Liver Disease

Saldarriaga

Freiberg²,

Krishnan³

et al. 2020

Hepatol Commun

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Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared with stellate cells, the role of macrophages in the development of fibrosis remains unclear. Multispectral imaging allows detection of multiple markers in situ in human formalin-fixed, paraffinembedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues, as it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preservation of hepatic architecture. We analyzed five different antibodies commonly observed on macrophage populations (CD68, MAC387, CD163, CD14, and CD16). After optimization of the monoplex stains and development of a Spectral Library, we combined all of the antibodies into a multiplex protocol and used them to stain biopsies collected from representative patients with chronic liver diseases, including chronic hepatitis C, nonalcoholic steatohepatitis, and autoimmune hepatitis. Various imaging modalities were tested, including cell phenotyping, tissue segmentation, t-distributed stochastic neighbor embedding plots, and phenotype matrices that facilitated comparison and visualization of the identified macrophage and other cellular profiles. We then tested the feasibility of this platform to analyze numerous regions of interest from liver biopsies with multiple patients per group, using batch analysis algorithms. Five populations showed significant differences between patients positive for hepatitis C virus with advanced fibrosis when compared with controls. Three of these were significantly increased in patients with advanced fibrosis when compared to controls, and these included CD163+CD16+, CD68+, and CD68+MAC387+. Conclusion: Spectral imaging microscopy is a powerful tool that enables in situ analysis of macrophages and other cells in human liver biopsies and may lead to more personalized therapeutic approaches in the future. (Hepatology Communications 2020;4:708-723).

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Section: Discussionsupporting

confidence: 81%

Multispectral Imaging Enables Characterization of Intrahepatic Macrophages in Patients With Chronic Liver Disease

Saldarriaga

Freiberg²,

Krishnan³

et al. 2020

Hepatol Commun

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“…The identification of a CD68+CD14+ cell population thought to have pro-inflammatory, immunoregulatory, and patrolling type functions, similar to previous findings in tolerogenic livers, and a recent study of human intrahepatic macrophages that analyzed these populations with single-cell RNA sequencing (7,15). This study also confirmed the accumulation of different macrophage populations (Suppl Fig 4) that were previously shown to be increased in patients with chronic HCV or in human monocytes cultured with HCV-infected hepatocytes (5,12,13,32,37).…”

Section: Discussionsupporting

confidence: 87%

“…HCV induces activation of signaling pathways that promote alternative macrophage activation (M2) and results in increased expression of pro-(M1) and anti-inflammatory (M2) cytokines (12,13), which enhances overall hepatic inflammation and development of fibrosis by promoting differentiation of hepatic stellate cells (11,13). However, it is now widely accepted that the "M1" and "M2" classification for macrophages is an over simplification since they exhibit extensive plasticity and change between homeostatic and pathologic conditions (14,15).…”

Section: Introductionmentioning

confidence: 99%

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

Saldarriaga

Booth

Freiberg

et al. 2019

Preprint

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List of Abbreviations:AIH: autoimmune hepatitis FFPE: formalin-fixed, paraffin-embedded H&E: Hematoxylin and eosin 2 HCV: hepatitis C virus IHC: immunohistochemical LSEC: liver sinusoidal endothelial cells MHAI: Modified hepatitis activity index NASH: nonalcoholic steatohepatitis PASD: Periodic acid-Schiff with diastase ROI: regions of interest TSA: tyramide signal amplification t-SNE: t-distributed stochastic neighbor embedding ABSTRACT Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markers in situ in human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and the in vivo hepatic milieu.We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), profibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and antiinflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis.Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.

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“…This was further confirmed by the high expression of transcripts enriched in Kupffer cells: Clec4f, Timd4 (Tim4), CD68, CD163, Siglec1 (CD169), Marco, Fcgr1 and Fcgr4 . The expression of genes characteristic of recruited monocyte‐derived macrophages [Itgam (CD11b), Cxcl10] and monocyte adhesion and migration‐promoting proteins (Lama4, Itga6) was considerably lower compared to the β‐gal − F4/80 high macrophages. Interestingly, the β‐gal + F4/80 high cells were characterized by high expression of microglial markers TREM2 and Aif‐1 (Iba‐1) , TYROBP (DAP12), the key signalling adaptor associated with TREM2 and TREM2‐shedding metalloproteinases ADAM10 and ADAM17.…”

Section: Resultsmentioning

confidence: 74%

Endogenous beta‐galactosidase activity marks a TREM2‐expressing Kupffer cell population in injured livers of Lgr5‐LacZ and wild‐type mice

et al. 2019

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Lgr5‐LacZ mice harbor the Escherichia coli LacZ gene encoding β‐galactosidase (β‐gal) under the control of the Lgr5 promoter, a stem/progenitor cell marker. In injured livers of Lgr5‐LacZ mice, cells expressing β‐galactosidase (β‐gal) are considered as potential bipotent liver progenitors; however, their origin and identity remain unknown. Unexpectedly, using lineage tracing, we demonstrate that the β‐gal+ cells do not originate from liver parenchymal cells. Instead, β‐gal+ cells, isolated from injured livers of both Lgr5‐LacZ and wild‐type mice, are positive for markers of Kupffer cells, liver‐resident macrophages. The β‐gal expression in these cells is a result of elevated expression of the endogenous beta‐galactosidase Glb1. In injured livers of Lgr5‐LacZ mice, bacterial β‐gal expression is very low, suggesting transgene silencing. The gene expression profile of the β‐gal+ Kupffer cells from injured livers suggests a role in liver regeneration.

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The Role of Myeloid-Derived Cells in the Progression of Liver Disease

Cited by 79 publications

References 257 publications

Multispectral Imaging Enables Characterization of Intrahepatic Macrophages in Patients With Chronic Liver Disease

Multispectral Imaging Enables Characterization of Intrahepatic Macrophages in Patients With Chronic Liver Disease

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

Endogenous beta‐galactosidase activity marks a TREM2‐expressing Kupffer cell population in injured livers of Lgr5‐LacZ and wild‐type mice

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