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Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

TitleProteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.
Publication TypeJournal Article
Year of Publication2014
AuthorsKallis YN, Scotton CJ, Mackinnon AC, Goldin RD, Wright NA, Iredale JP, Chambers RC, Forbes SJ
JournalPLoS One
Volume9
Issue1
Paginatione86241
Date Published2014
ISSN1932-6203
Abstract

Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1) is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

DOI10.1371/journal.pone.0086241
Alternate JournalPLoS ONE
PubMed ID24475094
PubMed Central IDPMC3903514
Grant List071124 / / Wellcome Trust / United Kingdom
14895 / / Cancer Research UK / United Kingdom
G0500428 / / Medical Research Council / United Kingdom
Publication institute
CRM