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Review
. 2025 Jan;99(1):103-114.
doi: 10.1007/s00204-024-03892-2. Epub 2024 Nov 6.

The emerging role of alternatively activated macrophages to treat acute liver injury

Chris Humphries  1 , Melisande L Addison  1   2 , James W Dear  1 , Stuart J Forbes  3
Affiliations
Review

The emerging role of alternatively activated macrophages to treat acute liver injury

Chris Humphries et al. Arch Toxicol. 2025 Jan.

Abstract

Acute liver injury (ALI) has a clear requirement for novel therapies. One emerging option is the use of alternatively activated macrophages (AAMs); a distinct subtype of macrophage with a role in liver injury control and repair. In this comprehensive review, we provide an overview of the current limited options for ALI, and the potential advantages offered by AAMs. We describe the evidence supporting their use from in vitro studies, pre-clinical animal studies, and human clinical trials. We suggest why the first evidence for the clinical use of AAMs is likely to be found in acetaminophen toxicity, and discuss the specific evidence for AAM use in this population, as well as potential applications for AAMs in other patient populations. The key domains by which the performance of AAMs for the treatment of ALI will be assessed are identified, and remaining challenges to the successful delivery of AAMs to clinic are explored.

Keywords: Acetaminophen overdose; Cell therapy; Inflammation; Liver injury; Liver regeneration; Macrophages.

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Conflict of interest statement

Declarations. Conflict of interest: All authors are beneficiaries of Medical Research Council UK funding for the MAIL Trial (ISRCTN 12637839). JD: MRC funding (and patent filed) for an in vitro diagnostic which could be a companion diagnostic, CSO funding for another clinical trial for treatment of paracetamol overdose, scientific advisory board member for EU funded TransBioLine consortium. SJF: founder and scientific advisor of Resolution Therapeutics Ltd. CH: grants from the Centre for Precision Cell Therapy for the Liver, member of the Royal College of Emergency Medicine toxicology advisory group.

Figures

Fig. 1
Fig. 1
The mechanisms by which AAMs are thought to produce their effect in ALI. (1) Phagocytosis of necrotic tissue by AAMs; (2) promotion of hepatocyte and endothelial tissue proliferation; (3) the pro-inflammatory immune response is downregulated via AAM cytokine release. Image created with biorender.com
Fig. 2
Fig. 2
Key domains by which the performance of AAMs for the treatment in ALI will be assessed are focussed on safety and efficacy. For safety: there must be no clinical concern for dose-limiting toxicity, the impact of any anti-HLA antibody formation on transplant suitability, immunogenicity (e.g. macrophage activation syndrome, transfusion-associated graft versus host disease), or off-target effects on other tissues. For efficacy: the mechanism of action must have robust pre-clinical studies to support the claims, biomarker studies will be required (and may require historic controls, or novel methods of interpretation). *Pharmacokinetic studies and tissue biopsy may not be achievable in clinical trials of patients with ALI for clinical and ethical reasons. Image created with biorender.com
See this image and copyright information in PMC

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