Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

Yang, Ai-Ting; Kim, Yong-Ook; Yan, Xu-Zhen; Abe, Hiroyuki; Aslam, Misbah; Park, Kyoung-Sook; Zhao, Xin-Yan; Jia, Ji-Dong; Klein, Thomas; You, Hong; Schuppan, Detlef

doi:10.1016/j.jcmgh.2022.12.005

Cited by 144Liver physiology and pathologyPeptidase Inhibition and AnalysisLiver Disease Diagnosis and Treatment

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

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Yang, Ai-Ting, Kim, Yong-Ook, Yan, Xu-Zhen, Abe, Hiroyuki, Aslam, Misbah, Park, Kyoung-Sook, Zhao, Xin-Yan, Jia, Ji-Dong +3 more·2023·Cellular and Molecular Gastroenterology and Hepatology

DOI 10.1016/j.jcmgh.2022.12.005PMC PMC9972574

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Abstract

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

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Partial polarization of macrophages toward a restorative phenotype, characterized by downregulation of pro-inflammatory markers without changes in Arg1 expression, was observed during fibrosis progression but not during regression.
“Partial polarization of macrophages toward a restorative phenotype -characterized by downregulation of pro-inflammatory markers without changes in Arg1 expression- was observed during fibrosis progression but not during regression.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [88]
The Results section, “FAP Inhibition Attenuates Macrophage Infiltration and Activation in Liver Fibrosis” (page unavailable), reports that FAP inhibition suppressed ccl2 and inos during fibrosis progression while arg1 remained unchanged; during regression, macrophage measures remained unchanged. It also reports reduced macrophage numbers and suppression of the anti-inflammatory marker ym1, interpreting the findings as reduced recruitment and activation—not polarization toward a restorative phenotype. (LLM, conf=0.87)
Experimental — accuracy not yet measured
In a biliary fibrosis model (Mdr2-/- mice), FAP inhibition improved liver fibrosis although macrophages displayed a mixed phenotype, with upregulation of both pro-inflammatory and tolerogenic markers.
“Using a similar approach in a biliary fibrosis model (Mdr2-/- mice), FAP inhibition also improved liver fibrosis although macrophages displayed a mixed phenotype, with upregulation of both pro-inflammatory and tolerogenic markers.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [88]
The Results sections on biliary fibrosis report reduced liver collagen and modest beneficial remodeling after FAP inhibition in Mdr2−/− mice. They also report increased M2-type macrophage markers (ARG1 and YM1), but not the claimed upregulation of pro-inflammatory markers: iNOS and CCL2 were unchanged. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In vitro, human THP-1 monocytes exposed to conditioned media from LX2 cells pretreated with a FAP inhibitor exhibited reduced activation, with downregulation of iNOS, TGFβ1, MMP9 and MMP14, and upregulation of MMP1, along with a trend toward increased IL-10 expression.
“In complementary in vitro experiments, human THP-1, monocytes exposed to conditioned media from LX2 cells pretreated with a FAP inhibitor exhibited reduced activation, with downregulation of iNOS, TGFβ1, MMP9 and MMP14, and upregulation of MMP1, along with a trend toward increased IL-10 expression.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [88]
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Inhibition of FAP, expressed in a subset of myofibroblasts including HSCs, attenuates parenchymal liver fibrosis and increases hepatocyte proliferation.
“Yang et al. (88) inhibited fibroblast activation protein (FAP), which is expressed in a subset of myofibroblasts, including HSCs, and observed attenuation of parenchymal liver fibrosis together with increased hepatocyte proliferation.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [88]
FAP inhibition was effective in limiting fibrogenesis but did not promote fibrosis resolution.
“Consistently, FAP inhibition was effective in limiting fibrogenesis but did not promote fibrosis resolution.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [88]

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Fibroblast activation protein-α in liver fibrosis and hepatocarcinogenesis: Stromal remodeling, molecular imaging, and theranostic targeting
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Authors: Yang, A.-T., Kim, Y.-O., Yan, X.-Z., Abe, H., Aslam, M., Park, K.-S., Zhao, X.-Y., Jia, J.-D., Klein, T., You, H., & Schuppan, D.
Affiliations: University Medical Center of the Johannes Gutenberg University Mainz (DE)
Boehringer Ingelheim (Germany) (DE)
Capital Medical University (CN)
Beth Israel Deaconess Medical Center (US)
Corresponding author: Schuppan, Detlef
ORCID: Klein, Thomas
You, Hong
Schuppan, Detlef
Venue: Cellular and Molecular Gastroenterology and Hepatology
Publisher: Elsevier BV
Published: 2023
Volume: 15
Issue: 4
Pages: 841-867
ISSN: 2352-345X (ISSN-L)
DOI: 10.1016/j.jcmgh.2022.12.005
PMC: PMC9972574
OpenAlex: W4311422489
Cited by: 144
References: 53
Citations by year: 2026: 40 · 2025: 47 · 2024: 38 · 2023: 18
FWCI: 15.32
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Deutsche Forschungsgemeinschaft (SFB 1066, CRC 1292)
Horizon 2020 (634413, 777377)
National Natural Science Foundation of China (82130018, 81970524)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords: fibroblast activation protein, liver fibrosis, hepatic stellate cells, macrophage activation, M2 macrophages, myofibroblasts, collagen deposition, hepatocyte proliferation, biliary fibrosis, carbon tetrachloride, desmoplasia
MeSH terms: Animals, Carbon Tetrachloride, Collagen, Fibroblasts, Fibrosis, Hepatitis, Humans, Inflammation, Liver Cirrhosis, Liver Diseases, Macrophages, Mice

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Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

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