Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

Martina Casari; Dominik Siegl; Carsten Deppermann; Detlef Schuppan

doi:10.3389/fimmu.2023.1277808

Macrophages and platelets in liver fibrosis and hepatocellular carcinoma

Front Immunol. 2023 Dec 5:14:1277808. doi: 10.3389/fimmu.2023.1277808. eCollection 2023.

Authors

Martina Casari¹, Dominik Siegl², Carsten Deppermann^{1

3}, Detlef Schuppan^{2

3

4}

Affiliations

¹ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
² Institute for Translational Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
³ Research Center for Immune Therapy Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
⁴ Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Abstract

During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible process, however, from the cirrhotic stage, there is significant progression to hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) and monocyte-derived macrophages are important drivers of fibrosis progression, but can also induce its regression once triggers of chronic inflammation are eliminated. In liver cancer, they are attracted to the tumor site to become tumor-associated macrophages (TAMs) polarized towards a M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis and hemostasis, platelets can also stimulate fibrosis and tumor development by secreting profibrogenic factors and regulating the innate immune response, e.g., by interacting with monocytes and macrophages. Here, we review recent literature on the role of macrophages and platelets and their interplay in liver fibrosis and hepatocellular carcinoma.

Keywords: Kupffer cell; MASH; MMP; angiogenesis; collagen; endothelial cell; monocyte; myofibroblast.

Publication types

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

MeSH terms

Carcinoma, Hepatocellular* / pathology
Esophageal and Gastric Varices* / metabolism
Esophageal and Gastric Varices* / pathology
Fibrosis
Gastrointestinal Hemorrhage
Humans
Liver Cirrhosis
Liver Neoplasms* / pathology
Macrophages

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. CD and DeS received project-related funding from the German Research Foundation (DFG) Collaborative Research Center (CRC) 1292, Project Number 318346496, SFB1292/2 TP08. DeS obtained further funding from CRC 1066/3 project B3 and, and by EU Horizon 2020 project under grant agreements nr. 777377 (LITMUS, Liver Investigation on Marker Utility in Steatohepatitis).