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Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis¹

Jonathan A. Fallowfield^*, Masashi Mizuno, Timothy J. Kendall^*, Christothea M. Constandinou, R. Christopher Benyon^*, Jeremy S. Duffield and John P. Iredale^2,

^* Liver Research Group, Southampton General Hospital, Southampton, United Kingdom; Renal Division, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115; Cancer Research U.K. Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom; and Medical Research Council/University of Edinburgh Centre for Inflammation Research, Edinburgh, United Kingdom

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 CCl₄ injury, we found that SAM depletion resulted in a 5-fold reduction in mmp13 message (p = 0.005). Furthermore, resolution of CCl₄-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Medical Research Council U.K. (to J.A.F., J.P.I., and R.C.B.); Wellcome Trust U.K. (to T.J.K.); National Institutes of Health Grant DK73299 (to J.S.D.); and also by generous donations from the estates of the late Victor Lyons and the late John Clarke.

² Address correspondence and reprint requests to Dr. John P. Iredale, Medical Research Council/University of Edinburgh Centre for Inflammation Research, Little France Way, Edinburgh, U.K. E-mail address: John.Iredale{at}ed.ac.uk

³ Abbreviations used in this paper: SAM, scar-associated macrophage; MMP, matrix metalloproteinase; HSC, hepatic stellate cell; TIMP, tissue inhibitor of metalloproteinase; DT, diphtheria toxin; LCM, laser capture microdissection; WT, wild type; dig, digoxigenin; HPF, high power field.

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