title: Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis.
abstract: Both the identity and source of the rodent collagenase(s) that mediates matrix remodeling in liver fibrosis remain elusive. We have recently demonstrated an unequivocal role for scar-associated macrophages (SAMs) in the spontaneous resolution of liver fibrosis and sought to determine whether SAMs are the source of matrix metalloproteinase (MMP) 13 (collagenase 3), considered to be the primary interstitial collagenase in rodents. In this study, we demonstrate an association between MMP13 expression and the presence of SAMs in the regression of experimental liver fibrosis. mmp13 gene expression was restricted to regions of fibrosis that were rich in SAMs. Both MMP13 mRNA and protein colocalized to large phagocytes within and directly apposed to hepatic scars. Using the CD11b-DTR-transgenic mouse to deplete SAMs in a model of chronic CCl(4) injury, we found that SAM depletion resulted in a 5-fold reduction in mmp13 message (p = 0.005). Furthermore, resolution of CCl(4)-induced fibrosis was retarded in MMP13-deficient mice. Thus, SAMs selectively, during resolution of fibrosis induce and use the major collagenase MMP13 to mediate the resorption of interstitial matrix and successfully remodel the fibrotic liver.
authors.affiliation: Liver Research Group, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fallowfield
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kendall
authors.forename: Christothea M
authors.initials: CM
authors.lastname: Constandinou
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Benyon
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002921:Cicatrix / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000201:enzymology* / Q000502:physiology; D053509:Matrix Metalloproteinase 13 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D012333:RNA, Messenger; D002251:Carbon Tetrachloride; D053509:Matrix Metalloproteinase 13