Functional role of chemokines in liver disease models

Abstract

Chemokines are a class of small cytokine-like molecules that orchestrate immune cell infiltration into the liver in response to acute and chronic injuries. Apart from their chemotactic effect, however, chemokines seem to mediate many other aspects of liver diseases, including a direct activation of stellate cells, the modulation of hepatocyte proliferation and angiogenesis. The identification of specific biological functions for chemokines in liver diseases has been hampered by the finding that resident and infiltrating cells in the liver are often a source, as well as a target, of chemokines. Furthermore, chemokines might cause differing effects depending on the etiology of liver damage, their local concentrations and their ability to form multimers and heterodimers. Nevertheless, the functions of a number of important chemokines and their associated receptors have been identified in both in vivo and in vitro studies. Indeed, harmful (proinflammatory, profibrogenic) and beneficial (antifibrogenic, antiangiogenic) effects of chemokines have been discovered in experimental liver disease models. In this Review, the current knowledge of chemokines in experimental liver disease models is summarized. Advances that might lead to preclinical applications are discussed, as are the roles of chemokine receptors as promising pharmacologically targetable molecules.

Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis

“…This finding is in keeping with the known ability of monocytes and macrophages to change phenotype in situ depending on local environmental cues (13). These findings have implications for development of antifibrotic therapies, where targeting inflammatory monocyte recruitment might adversely impact on the population of restorative Ly-6C lo macrophages (39,57). This finding provides an explanation for the apparently counterintuitive observation made in the work by Mitchell et al (58): that decreased CCR2-dependent recruitment of Ly-6C hi monocytes retards fibrosis resolution (58).…”

“…The proinflammatory macrophage population was enriched for pathways, including response to wounding, coagulation cascade, and chemotaxis (Fig. S6A), which are important for fibrogenesis (38,39). Analysis of the restorative macrophages showed enrichment for pathways, such as lysosomes, endocytosis, scavenger receptors, and antigen presentation, which are implicated in phagocytosis (Fig.…”

Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure

“…31 Considering liver cell populations, FPR1 is constitutively expressed by neutrophils, Kupffer cells, and hepatocytes, 32 which also express CXCR2. 33 In this sense, blockage of these receptors in vivo may also directly affect these cells and may account partially for the observed effects. In our hands, we could not observe any significant protection by adding these antagonists to isolated HepG2 cells.…”

An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

“…28 A more recent report indicate that MCP-1 can activate and transdifferentiate portal fibroblasts to myofibroblasts via a distinct receptor other than CCR2, 5 and induce collagen production in portal fibroblasts in a paracrine manner. These observations not only strengthen the role of inflammation in fibrogenesis, but also pinpoint MCP-1 as a key molecular link between the infiltration of immune cells and the production of collagen.…”