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An Ectopic Chemokine Expression Model for Testing Macrophage Recruitment In Vivo
Published on: September 25, 2019
Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver
Mark A Barnes1, Megan R McMullen1, Sanjoy Roychowdhury1
1Departments 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.
Abstract:
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.
Insights
Macrophage migration and function, regulated by MIF (macrophage migration inhibitory factor), are crucial for resolving liver fibrosis. MIF deficiency impairs resolution by reducing pro-resolution macrophages and ECM degradation.
Area of Science:
- Immunology
- Hepatology
- Fibrosis Research
Background:
- Peripheral monocyte recruitment to the liver is vital for injury response.
- Macrophage migration inhibitory factor (MIF) acts as a chemokine and cytokine, modulating innate immunity.
- Hepatic fibrosis involves extracellular matrix (ECM) accumulation and HSC activation.
Purpose of the Study:
- To investigate the role of MIF in CCl4-induced hepatic fibrosis progression.
- To determine how MIF influences hepatic immune responses and HSC activation.
- To elucidate the impact of MIF on SAM (scavenger-associated macrophage) recruitment and function.
Main Methods:
- Chronic carbon tetrachloride (CCl4) administration to wild-type (WT) and MIF-deficient (MIF(-/-)) female mice.
- Analysis of fibrosis markers, including alpha-smooth muscle actin (αSMA) and collagen 1α1 mRNA and protein.
- Assessment of SAM recruitment, phenotype, and ECM-degrading enzyme expression (e.g., MMP13).
Main Results:
- MIF(-/-) mice exhibited blunted HSC activation and αSMA expression compared to WT mice.
- Despite reduced HSC activation, ECM accumulation was similar, suggesting impaired ECM degradation in MIF(-/-) mice.
- MIF(-/-) mice showed decreased SAM recruitment, particularly pro-resolution macrophages, correlating with lower MMP13 expression.
Conclusions:
- MIF-dependent SAM recruitment is critical for ECM degradation during liver fibrosis resolution.
- The phenotypic profile of macrophages, influenced by MIF, impacts fibrosis resolution.
- Targeting MIF-mediated macrophage recruitment may offer therapeutic strategies for liver fibrosis.
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