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Cited by 12Liver physiology and pathologyMacrophage Migration Inhibitory FactorMesenchymal stem cell research

Protozoan‐Derived Cytokine‐Transgenic Macrophages Reverse Hepatic Fibrosis

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Chen, Ying, Wang, Jie, Zhou, Nan, Fang, Qi, Cai, Haijian, Du, Zhuoran, An, Ran, Liu, Deng +6 more·2024·Advanced Science
DOI 10.1002/advs.202308750PMC PMC10987136
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Abstract

Macrophage therapy for liver fibrosis is on the cusp of meaningful clinical utility. Due to the heterogeneities of macrophages, it is urgent to develop safer macrophages with a more stable and defined phenotype for the treatment of liver fibrosis. Herein, a new macrophage‐based immunotherapy using macrophages stably expressing a pivotal cytokine from Toxoplasma gondii , a parasite that infects ≈ 2 billion people is developed. It is found that Toxoplasma gondii macrophage migration inhibitory factor‐transgenic macrophage (Mφ tgmif ) shows stable fibrinolysis and strong chemotactic capacity. Mφ tgmif effectively ameliorates liver fibrosis and deactivates aHSCs by recruiting Ly6C hi macrophages via paracrine CCL2 and polarizing them into the restorative Ly6C lo macrophage through the secretion of CX3CL1. Remarkably, Mφ tgmif exhibits even higher chemotactic potential, lower grade of inflammation, and better therapeutic effects than LPS/IFN‐γ‐treated macrophages, making macrophage‐based immune therapy more efficient and safer. Mechanistically, Tg MIF promotes CCL2 expression by activating the ERK/HMGB1/NF‐κB pathway, and this event is associated with recruiting endogenous macrophages into the fibrosis liver. The findings do not merely identify viable immunotherapy for liver fibrosis but also suggest a therapeutic strategy based on the evolutionarily designed immunomodulator to treat human diseases by modifying the immune microenvironment.

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  • Transgenic macrophages expressing TgMIF can systemically recruit and polarize endogenous monocytes/macrophages towards a reparative phenotype with low inflammation, thereby remodeling the microenvironment.

    “For example, transgenic macrophages expressing Toxoplasma gondii macrophage migration inhibitory factor (TgMIF) can systemically recruit and polarize endogenous monocytes/macrophages towards a reparative phenotype with low inflammation, thereby remodeling the microenvironment (76).”

    From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [76]

    The Results section on monocyte-derived macrophage recruitment (page not provided) reports that TgMIF-expressing macrophages recruited host macrophages into fibrotic mouse livers and promoted their switch to restorative Ly6Clo macrophages. The Results also describe lower pro-inflammatory potential than macrophages expressing mammalian MIF. The paper supports remodeling of the hepatic immune microenvironment, but not recruitment throughout the body as “systemically” suggests. (LLM, conf=0.86)

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Authors
Chen, Y., Wang, J., Zhou, N., Fang, Q., Cai, H., Du, Z., An, R., Liu, D., Chen, X., Wang, X., Li, F., Yan, Q., Chen, L., & Du, J.
Affiliations
  • Anhui Medical University (CN)
  • First Affiliated Hospital of Anhui Medical University (CN)
  • Wannan Medical College (CN)
  • Guangzhou Laboratory (CN)
  • Department of Biochemistry and Molecular Biology Research Center for Infectious Diseases School of Basic Medical Sciences Anhui Medical University Hefei 230032 China
Corresponding author
  • Chen, Lijian
  • Du, Jian
ORCID
Venue
Advanced Science
Publisher
Wiley
Published
2024-01-21
Volume
11
Issue
13
Pages
e2308750-e2308750
ISSN
2198-3844 (ISSN-L)
DOI
10.1002/advs.202308750
PMC
PMC10987136
OpenAlex
W4391108324
Cited by
12
References
53
Citations by year
2026: 5 · 2025: 3 · 2024: 4
FWCI
3.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82272360, 81871674, 82270644, 81970542)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
liver fibrosis, Toxoplasma gondii, macrophage migration inhibitory factor, hepatic stellate cells, MCP-1, fractalkine, fibrinolysis, chemotaxis, immune microenvironment
MeSH terms
Humans, Inflammation, Liver Cirrhosis, Macrophages, Phenotype, Toxoplasma

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