SUMMARY AND FUTURE GOALS
It is clear that macrophages are critically involved in both the induction and resolution of fibrosis. Seemingly slight modifications in the pattern of MMP expression can dramatically affect outcomes, with macrophage-derived MMP12 enhancing fibrosis whereas MMP1 and MMP13 display potent antifibrotic activity.166,167 To promote fibrosis, macrophages produce specific MMPs, like MMP9, that degrade the basement membrane and allow inflammatory cells and recruited fibroblasts to enter sites of injury. They also secrete a variety of profibrotic mediators including TGF-β1, PDGF, and many chemokines that recruit and activate inflammatory cells. To negatively regulate fibrosis, macrophages secrete factors that induce myofibroblast apoptosis, remove cellular debris that otherwise perpetuates inflammation, engulf and digest ECM components, and stimulate the production of collagen-degrading MMPs in other cell types including stellate cells, myofibroblasts, and neutrophils. Macrophage-mediated changes in the ECM can also affect the survival of myofibroblasts and so facilitate the termination of progressive fibrosis.175 By expressing Arg-1, macrophages also deplete an essential amino acid that CD4+ T cells and myofibroblasts require to proliferate, thereby facilitating the down-regulation of profibrotic immune responses.91 These observations are consistent with many recent studies that have suggested macrophages are essential to the resolution of fibrosis.
Therefore, although myofibroblasts are typically thought of as the “master mediators” of fibrosis because they synthesize collagen and other ECM components, macrophages play an equally important role by serving as the “master regulators” of myofibroblast function and ECM degradation. A key goal of future research will be to determine when and how distinct subpopulations of macrophages control these disparate functions or whether the same macrophage population can adjust its phenotype over time in coordination with new stimuli found in the local milieu. It will be especially important to test whether recovering from fibrosis requires recruiting a new class of macrophage from the bone marrow.51 In addition to specifying which macrophage subpopulations promote, inhibit, or reverse fibrosis, future research should also elucidate the signals that regulate macrophage phenotypic conversion, differentiation, and recruitment. With our growing appreciation of the complex role of macrophages in fibrogenesis, the global depletion of macrophages no longer seems a viable option to treat highly progressive and established disease.19 Instead, future efforts should focus on identifying the specific macrophage subpopulations that facilitate the resolution and reversal fibrosis as well as their specific mechanism of action.
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