In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 46 ( 2012-11-13)
Abstract:
In summary, we identified here a distinct monocyte-derived Ly-6C lo macrophage population that orchestrates the regression of hepatic fibrosis. Our findings that this macrophage population is generated from a phenotypic switch in the profibrotic macrophage subset that is induced by the phagocytosis of cellular debris has enabled us to develop a therapeutic strategy to manipulate macrophage phenotype in vivo and accelerate the resolution of hepatic fibrosis. Thus, these data suggest a potential treatment for this pathological process. We, therefore, postulated that phagocytosis might induce this observed switch in macrophage phenotype favoring fibrosis regression. We confirmed the postphagocytic nature of the murine restorative macrophage population in vivo and proceeded to model this finding in vitro by inducing a similar matrix-degrading phenotype in macrophages by the phagocytosis of cellular debris. This phenotype was, at least in part, dependent on phagocytosis-induced activation of ERK signaling in macrophages, one of numerous pathways that can regulate cellular responses. Finally, we used these data to develop a therapeutic strategy. By administering liposomes during fibrosis regression in mice, we induced phagocytic behavior in macrophages and thus, were able to manipulate the hepatic macrophage phenotype, reducing profibrotic Ly-6C hi macrophages and increasing restorative Ly-6C lo macrophages, which resulted in accelerated resolution of hepatic fibrosis ( Fig. P1 ). We next conducted experiments to more extensively characterize this population to develop a therapeutic strategy. Principally, we determined that this restorative macrophage population derives from recruited inflammatory monocytes. This finding shows that the proresolution macrophage shares a common origin with the profibrotic Ly-6C hi macrophage population and indicates that macrophages undergo a phenotypic switch in situ. Moreover, this switch occurs after active proliferation of the infiltrating Ly-6C hi monocyte-derived macrophages. Gene expression profiling of profibrotic and restorative macrophage subsets showed that the Ly-6C hi population expressed high levels of proinflammatory cytokines and chemokines, whereas the restorative Ly-6C lo subset expressed high levels of specific growth factors and matrix-degrading metalloproteinases to mediate an antifibrotic effect and promote hepatocyte proliferation. Additional analysis showed increased levels of expression of opsonins and phagocytosis receptors in restorative macrophages, indicative of a role for these cells in the clearance of cellular debris from the inflamed liver ( Fig. P1 ). We also succeeded in identifying an analogous macrophage population in cirrhotic human liver. We used chronic carbon tetrachloride (CCl 4 ) to induce liver fibrosis in mice. This scar tissue resolves spontaneously after the cessation of injury. We determined that the Ly-6C lo macrophage population accumulated principally in the liver at the time of maximal fibrosis resolution and represented the main source of scar-degrading matrix metalloproteinase enzymes. Furthermore, selective depletion of this Ly-6C lo macrophage population during fibrosis regression caused a failure of scar remodeling, identifying it as the restorative macrophage. Macrophages, central orchestrators of the innate immune response, are critical for both fibrosis formation and regression ( 3 ) in several organ systems. These divergent effects reflect the known heterogeneity of macrophages, which are capable of adopting vastly distinct phenotypes depending on the stimuli to which they are exposed. Macrophages are, thus, often identified as classically activated proinflammatory cells (M1) or alternatively activated cells with immunomodulatory and wound-healing properties (M2). However, this binary classification cannot represent the more complex heterogeneity in vivo ( 4 ). Functional characterization of macrophages involves determining the differential expression of cell surface markers to identify distinct subsets. Ly-6C is widely used to identify functionally distinct murine monocyte populations in the circulation, and more recently, it has shown use in defining distinct macrophage subsets in tissue. Indeed, a Ly-6C hi monocyte-derived macrophage population is profibrogenic in the liver ( 5 ). In our current study, we used differential Ly-6C expression on hepatic macrophages to identify a distinct Ly-6C lo subset that is responsible for mediating the regression of fibrosis. Diseases involving tissue fibrosis, the common endpoint to chronic injury, contribute to up to 45% of all deaths in industrialized nations ( 1 ). Emerging evidence acquired for different organs, particularly chronically injured liver, indicates that fibrosis is potentially reversible ( 2 ). The key mechanisms involved in the regression of fibrosis, although far from being fully defined, include apoptosis of scar-producing myofibroblasts and degradation of scar tissue by matrix metalloproteinase enzymes. Here, we report the identification of a specific subset of macrophages that is responsible for promoting the breakdown of the hepatic scar and hence, the restoration of normal tissue architecture. Furthermore, by characterizing this population, we developed a therapeutic strategy, where inducing phagocytosis, enabled manipulation of the macrophage phenotype in vivo and accelerated the regression of liver fibrosis.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1119964109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
