Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.
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.
Department of Hepatology, St. Mary's Hospital Campus, Imperial College London, London, United Kingdom.
Yiannis N
YN
Kallis
Centre for Inflammation & Tissue Repair, University College London, London, United Kingdom.
Christopher J
CJ
Scotton
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Alison C
AC
Mackinnon
Department of Histopathology, St. Mary's Hospital Campus, Imperial College London, London, United Kingdom.
Robert D
RD
Goldin
Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
Nicholas A
NA
Wright
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom ; MRC Centre for Regenerative Medicine, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
John P
JP
Iredale
Centre for Inflammation & Tissue Repair, University College London, London, United Kingdom.
Rachel C
RC
Chambers
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom ; MRC Centre for Regenerative Medicine, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Stuart J
SJ
Forbes
D000704:Analysis of Variance; D000818:Animals; D016026:Bone Marrow Transplantation; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002460:Cell Line; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D044463:Receptor, PAR-1; D002251:Carbon Tetrachloride