Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2020; 26(16): 1879-1887
Published online Apr 28, 2020. doi: 10.3748/wjg.v26.i16.1879
Regulation of macrophage activation in the liver after acute injury: Role of the fibrinolytic system
Katherine Roth, Jenna Strickland, Bryan L Copple
Katherine Roth, Jenna Strickland, Bryan L Copple, Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States
Author contributions: Roth K, Strickland J and Copple BL wrote the paper.
Supported by National Institutes of Health Grant, No. DK073566 (to Copple BL); and National Institutes of Health Training Grant, No. ES007255 (to Roth K and Strickland J).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Bryan L Copple, PhD, Associate Professor, Research Associate, Department of Pharmacology and Toxicology, Institute for Integrative Toxicology, Michigan State University, 1355 Bogue Street, East Lansing, MI 48824, United States.
Received: January 7, 2020
Peer-review started: January 7, 2020
First decision: March 6, 2020
Revised: March 31, 2020
Accepted: April 8, 2020
Article in press: April 8, 2020
Published online: April 28, 2020

The liver functions, in part, to prevent exposure of the body to potentially harmful substances ingested in the diet. While it is highly efficient at accomplishing this, it is frequently prone to liver injury due to the biotransformation of xenobiotics into toxic metabolites. To counter this injury, the liver has evolved a unique capacity to rapidly and efficiently repair itself. Successful resolution of acute liver injury relies on hepatic macrophage populations that orchestrate the reparative response. After injury, Kupffer cells, the resident macrophages of the liver, become activated and secrete proinflammatory cytokines. These cytokines recruit other immune cells, including monocyte-derived macrophages, to the liver where they contribute to the repair process. Monocyte-derived macrophages traffic into the necrotic foci where they rapidly phagocytose dead cell debris. Simultaneous with this process, these cells change phenotype from a proinflammatory macrophage to a pro-restorative macrophage that produce pro-mitogenic growth factors and anti-inflammatory cytokines. Ultimately this process triggers resolution of inflammation, and along with proliferation of other hepatic cells, restores the liver architecture and function. While the mechanisms regulating specific macrophage functions during repair remain to be elucidated, recent studies indicate a key role for the fibrinolytic system in coordinating macrophage function during repair. In this review, we will highlight the function and role of hepatic macrophages in repair after acute liver injury, and will discuss the role of the fibrinolytic enzyme, plasmin, in regulation of these various processes.

Keywords: Macrophage, Plasmin, Acetaminophen, Liver injury, Liver repair

Core tip: Macrophages contribute to repair of the liver after injury. After injury, Kupffer cells release cytokines that recruit monocyte-derived macrophages that phagocytose dead cell debris. These cells switch phenotype becoming pro-restorative macrophages that terminate cytokine synthesis and produce pro-mitogenic growth factors that facilitate liver repair.