Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice
Abstract
Urokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated macrophages were analysed histologically. Fibrinolytic activity at the damaged site was also examined by fibrin zymography. In wild-type mice, the extent of damage decreased gradually until day 14 and was associated with an accumulation of macrophages at the border of the damaged site. In addition, the macrophages that accumulated near the damaged tissue expressed CD206, a marker of highly phagocytic macrophages, on day 7. Further, macrophages that were adjacent to CD206-positive cells expressed inducible nitric oxide synthase (iNOS), a pro-inflammatory marker. u-PA activity increased at the damaged site on days 4 and 7, which distributed primarily at the border region. In contrast, in u-PA-deficient mice, the decrease in damage size and the accumulation of macrophages were impaired. Further, neither CD206 nor iNOS was expressed in the macrophages that accumulated at the border region in u-PA-deficient mice. Mice deficient for the gene encoding either u-PA receptor (u-PAR) or tissue-type plasminogen activator experienced normal recovery during liver repair. These data indicate that u-PA mediates the accumulation of macrophages and their phenotypic heterogeneity at the border of damaged sites through u-PAR-independent mechanisms.
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Seven days after photochemical injury to the liver, CD206+ cells are observed near the border of the injured site, although these cells were not verified specifically as Mp, and no other time-points were examined.
“Seven days after photochemical injury to the liver, CD206ϩ cells are observed near the border of the injured site [68], although these cells were not verified specifically as Mp, and no other time-points were examined.”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [68]
After excisional skin wounding in rats or photochemical liver injury in mice, only a fraction of the wound Mp expresses iNOS (10-15% positive at peak in skin).
“After excisional skin wounding in rats [56] or photochemical liver injury in mice [68], only a fraction of the wound Mp expresses iNOS (10 -15% positive at peak in skin), and the heterogeneity of the Mp population may be dependent on proximity to the injured site [68].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [68]
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- Authors
- Kawao, N., Nagai, N., Tamura, Y., Okada, K., Yano, M., Suzuki, Y., Umemura, K., Ueshima, S., & Matsuo, O.
- Affiliations
- Kindai University (JP)
- Nagahama Institute of Bio-Science and Technology (JP)
- Hamamatsu University School of Medicine (JP)
- Corresponding author
- Matsuo, Osamu
- Venue
- Thrombosis and Haemostasis
- Publisher
- Georg Thieme Verlag KG
- Published
- 2011
- Volume
- 105
- Issue
- 05
- Pages
- 892-900
- ISSN
- 0340-6245 (ISSN-L)
- 2567-689X
- OpenAlex
- W2023661176
- Cited by
- 17
- References
- 42
- Citations by year
- 2021: 1 · 2020: 1 · 2017: 2 · 2015: 1 · 2014: 2 · 2013: 6 · 2012: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thrombosis and Haemostasis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Grant-in-Aid for Young Scientists (20790182)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- urokinase, liver repair, macrophage accumulation, CD206, inducible nitric oxide synthase, fibrinolysis, tissue remodeling, uPA receptor, tissue plasminogen activator
- MeSH terms
- Mannose Receptor, Animals, Cell Movement, Gene Expression Regulation, Light, Liver, Liver Diseases, Macrophages, Mice, Inbred Strains, Phagocytosis, Receptors, Cell Surface, Rose Bengal, Urokinase-Type Plasminogen Activator, Wound Healing, Mice, Knockout, Inflammation Mediators, Models, Animal, Lectins, C-Type, Mannose-Binding Lectins, Mice, Nitric Oxide Synthase Type II
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