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Thromb Haemost 2011; 105(05): 892-900
DOI: 10.1160/TH10-08-0516
Wound Healing and Inflammation/Infection
Schattauer GmbH

Urokinase-type plasminogen activator contributes to heterogeneity of macrophages at the border of damaged site during liver repair in mice

Naoyuki Kawao
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
,
Nobuo Nagai
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
2   Department of Animal Bio-science, Faculty of Bio-science, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan
,
Yukinori Tamura
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
,
Kiyotaka Okada
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
,
Masato Yano
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
,
Yasuhiro Suzuki
3   Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan
,
Kazuo Umemura
3   Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan
,
Shigeru Ueshima
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
4   Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Japan
,
Osamu Matsuo
1   Department of Physiology, Kinki University Faculty of Medicine, Osakasayama, Japan
› Author Affiliations Financial support: This study was partly supported by a Grant-in-Aid for Young Scientists (B: 20790182) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and a Kinki University Research Grant.
Further Information

Publication History

Received: 09 August 2010

Accepted after major revision: 24 January 2011

Publication Date:
28 November 2017 (online)

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Summary

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.

Keywords

u-PA - macrophage accumulation - macrophage activation - macrophage heterogeneity - liver repair
 

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