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Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver
Juan Diego Sanchez Vasquez, … , Harry L.A. Janssen, Adam J. Gehring
Juan Diego Sanchez Vasquez, … , Harry L.A. Janssen, Adam J. Gehring
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e175241. https://doi.org/10.1172/JCI175241.
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Research Article Hepatology Immunology Infectious disease

Virus-associated inflammation imprints an inflammatory profile on monocyte-derived macrophages in the human liver

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Abstract

Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immune-tolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of patients with chronic hepatitis B who had active liver inflammation and were starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA-Seq mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and were unique from macrophage found in healthy or cirrhotic liver. iMacs retained their core transcriptional signature after inflammation resolved, indicating inflammation-mediated remodeling of the macrophage population in the human liver that may affect progressive liver disease and immunotherapy.

Authors

Juan Diego Sanchez Vasquez, Shirin Nkongolo, Daniel Traum, Valentin Sotov, Samuel C. Kim, Deeqa Mahamed, Aman Mehrotra, Anjali Patel, Diana Y. Chen, Scott Fung, Anuj Gaggar, Jordan J. Feld, Kyong-Mi Chang, Jeffrey J. Wallin, Ben X. Wang, Harry L.A. Janssen, Adam J. Gehring

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Figure 2

Identification and characterization of myeloid cells during liver inflammation.

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Identification and characterization of myeloid cells during liver inflam...
(A) CD68+ clusters were reclustered using UMAP dimensionality reduction for 5 patients across 3 time points (baseline, week 12, and week 24). (B) Feature plots depicting single-cell gene expression of individual myeloid genes (scale: log-transformed gene expression). (C) Violin plots of macrophage-defining genes. All selected genes have an adjusted P value of less than 0.05. (D) IMC depicting liver macrophages and CD8+ T cell colocalization in inflamed livers of patients with CHB. The portal region is outlined by yellow dotted lines. (E) Enrichment of liver macrophages depicted by the ratio of the portal divided by the lobular cell count/mm2 between inflamed (n = 28) and noninflamed (n = 6) liver tissue sections. Lobular enrichment values were multiplied by –100. P values were determined by a nonparametric Mann-Whitney U test (*P < 0.05, **P < 0.005, and ***P < 0.001). (F and G) Simple correlation analysis between portal CD8+ T cells/mm2 and (F) serum ALT levels and (G) iMacs/mm2 in patients with CHB. (H) Proximity analysis of CD8+ T cells and liver macrophages within 15 μm between inflamed (n = 28) and noninflamed (n = 6) liver tissue sections. P values were determined by nonparametric Wilcoxon test (*P < 0.05, **P < 0.005, and ***P < 0.001). (I) Multiplex IF images showing liver macrophages in inflamed liver of patients with CHB at inflammatory foci and noninflamed regions (n = 4). Original magnification, ×20. (J) Quantification of liver macrophages in inflamed liver of patients with CHB at inflammatory foci and noninflammatory regions. P values were determined by nonparametric Wilcoxon test (*P < 0.05, **P < 0.005, and ***P < 0.001).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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