T‐Cell Immunoglobulin and Mucin Domain‐Containing Protein‐4 Is Critical for Kupffer Cell Homeostatic Function in the Activation and Resolution of Liver Ischemia Reperfusion Injury
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Background and Aims: Liver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver‐resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T‐cell immunoglobulin and mucin domain‐containing protein‐4 (TIM‐4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model. Approach and Results: Fluorescence‐activated cell sorting results showed that TIM‐4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti‐TIM‐4 antibody depleted TIM‐4+ macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b+ macrophages. To determine the KC‐specific function of TIM‐4, we reconstituted clodronate‐liposome–treated mice with exogenous wild‐type or TIM‐4‐deficient KCs at either 0 hour or 24 hours postreperfusion. TIM‐4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6 hours postreperfusion), but also impairment of the inflammation resolution (at 7 days postreperfusion). In vitro analysis revealed that TIM‐4 promoted KC efferocytosis to regulate their Toll‐like receptor response by up‐regulating IL‐10 and down‐regulating TNF‐α productions. Conclusions: TIM‐4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.
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Previous work shows that TIM4 can act as an efferocytosis receptor and that TIM4 expression by liver macrophages is decreased in MASH.
“These findings are consistent with previous work showing that TIM4 can function as an efferocytosis receptor (21–23) and that TIM4 expression by liver macrophages is decreased in MASH (24–27).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [23]
The Introduction and Discussion describe TIM-4 as an efferocytosis co-receptor, and the Results show that it facilitates efferocytosis by Kupffer cells. The paper reports decreased liver TIM-4 after ischemia and in Kupffer cells after LPS stimulation, but does not report decreased expression in MASH. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious in vitro work shows TIM4 can mediate efferocytosis by normal liver resident macrophages (KCs).
“Previous in vitro studies have shown that T cell immunoglobulin and mucin domain containing 4 (TIM4; gene Timd4) can mediate efferocytosis by normal liver resident macrophages [Kupffer cells (KCs)] (21–23)”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [23]
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- Authors
- Ni, M., Zhang, J., Sosa, R., Zhang, H., Wang, H., Jin, D., Crowley, K., Naini, B., Reed, F. E., Busuttil, R. W., Kupiec‐Weglinski, J. W., Wang, X., & Zhai, Y.
- Affiliations
- University of California, Los Angeles (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Wang, Xuehao
- Zhai, Yuan
- ORCID
- Venue
- Hepatology
- Published
- 2021-08-10
- Volume
- 74
- Issue
- 4
- Pages
- 2118-2132
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC9060306
- OpenAlex
- W3160441943
- Cited by
- 80
- References
- 51
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 14 · 2023: 20 · 2022: 12 · 2021: 1
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (P01Al120944, P01AI120944)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK102110, R01DK107533, R01DK102110, R01DK119338, DK119338)
- Topics
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- TIM-4, Kupffer cells, hepatic ischemia-reperfusion injury, efferocytosis, inflammation resolution, macrophage homeostasis, Toll-like receptor response, IL-10, TNF-α, clodronate liposome depletion, hepatic macrophages
- MeSH terms
- Animals, Homeostasis, Inflammation, Kupffer Cells, Liver Diseases, Membrane Proteins, Tumor Necrosis Factor-alpha, Signal Transduction, Reperfusion Injury, Interleukin-10, Toll-Like Receptors, Mice
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