Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis.
Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM. SAMs dynamically regulate HSC activation and ECM degradation. To gain insight into the role of MIF in progression of liver fibrosis, we investigated markers of fibrosis and immune responses after chronic CCl4 administration to female C57BL/6 and MIF(-/-) mice. Chronic CCl4 exposure increased activation of HSC in WT mice, indicated by increased expression of αSMA mRNA and protein, as well as mRNA for collagen 1α1; these responses were blunted in female MIF(-/-) mice. Despite lower activation of HSC in MIF(-/-) mice, accumulation of ECM was similar in WT and MIF(-/-)mice, suggesting a decreased rate of ECM degradation. Recruitment of SAMs was lower in MIF(-/-) mice compared with WT mice, both in their initial inflammatory phenotype, as well as in the later phase as proresolution macrophages. The decreased presence of resolution macrophages was associated with lower expression of MMP13 in MIF(-/-) mice. Taken together, these data indicate that MIF-dependent recruitment of SAMs contributes to degradation of ECM via MMP13, highlighting the importance of appropriate recruitment and phenotypic profile of macrophages in the resolution of fibrosis.
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Mark A
MA
Barnes
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Megan R
MR
McMullen
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Sanjoy
S
Roychowdhury
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Nabil Z
NZ
Madhun
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Kathryn
K
Niese
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Mitchell A
MA
Olman
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Abram B
AB
Stavitsky
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA.
Richard
R
Bucala
Departments of *Molecular Medicine and Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; and Departments of Pathobiology and Gastroenterology and Hepatology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio, USA nagyL3@ccf.org.
Laura E
LE
Nagy
D000818:Animals; D002634:Chemotaxis, Leukocyte; D002921:Cicatrix; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008263:Macrophage Migration-Inhibitory Factors; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
MIF; carbon tetrachloride