Platelet-derived chemokines: New targets to treat liver fibrosis
Authors: Oriol Morales-Ibanez, Ramón Bataller
Journal: Journal of Hepatology (2010)

COMMENTARY ON: CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Zaldivar MM, Pauels K, von Hundelshausen P, Berres ML, Schmitz P, Bornemann J, Kowalska MA, Gassler N, Streetz KL, Weiskirchen R, Trautwein C, Weber C, Wasmuth HE. Hepatology 2010;51:1345–53. http://www.ncbi.nlm.nih.gov/pubmed/20162727 Hepatic fibrosis is the result of a complex interplay between resident hepatic cells, infiltrating inflammatory cells, and a number of locally-acting peptides called cytokines [[1]Bataller R. Brenner D.A. Liver fibrosis.J Clin Invest. 2005; 115: 209-218Crossref PubMed Scopus (4187) Google Scholar]. Cytokines are a family of proteins that function as mediators of cell communication. They include chemokines, interleukins, interferons, growth factors, angiogenic factors, vasoactive substances, soluble receptors, and soluble proteases [[2]Moreno M. Bataller R. Cytokines and renin-angiotensin system signaling in hepatic fibrosis.Clin Liver Dis. 2008; 12: 825-852Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]. Unregulated cytokine synthesis and release coordinate the hepatic response to injury and participate in the initiation, progression, and maintenance of fibrosis. Over the past few years, special attention has been paid to the role of chemokines as potential mediators and therapeutic targets for liver fibrosis. Chemokines are a group of cytokines that form a family of small and structurally related molecules that regulate cell trafficking (chemotaxis) of various classes of leucocytes. Their nomenclature and classification in four groups are based on the configuration of a conserved amino-proximal cysteine-containing motif. The CC chemokines have two juxtapositioned cysteine residues, the CXC chemokines contain a non-conserved aminoacid (X) between the two cysteine residues, the C chemokines contain a single cysteine residue, and the CX3C chemokines contain a non-conserved triplet of aminoacids between the two cysteine residues. There are more than 50 ligands and 19 receptors of the chemokine network. The CC and CXC families are the best characterized (Fig. 1). Their function seems to be based on their structure, as CC chemokines are, in general, chemotactic for mononuclear cells (monocytes and lymphocytes), whereas CXC chemokines are important neutrophil chemoattractants and angiogenesis inducers. Experimental and human evidence strongly suggest that chemokines play an important role in acute and chronic liver diseases, mediating the infiltration of inflammatory cells in the injured liver [[3]Wasmuth H.E. Tacke F. Trautwein C. Chemokines in liver inflammation and fibrosis.Semin Liver Dis. 2010; 30: 215-225Crossref PubMed Scopus (130) Google Scholar]. Besides this immune action, chemokines also regulate the biological properties of resident hepatic cells, such as the resistance of hepatocytes to cell death and the properties of non-parenchymal cells. In particular, chemokines are known to stimulate pro-inflammatory and fibrogenic actions of hepatic stellate cells (HSC), a major cell type involved in fibrogenesis. Although the chemokine system is highly redundant and chemokine receptors are promiscuous, genetic and/or pharmacological blockade of both chemokine ligands and receptors modifies the fibrogenic response to liver injury. Most chemokines studied (i.e. MCP-1, RANTES, interleukin-8, etc.) and their receptors contribute not only to the infiltration of inflammatory cells but also to the accumulation of extracellular matrix. Because many of these chemokines directly stimulate collagen synthesis by cultured HSC, it is likely that they exert a direct profibrogenic effect in the injured liver. Moreover, chemokines released by inflammatory cells induce hepatocellular death and can be important contributors to liver failure that develop in patients with advanced fibrosis. The source of chemokines during chronic liver diseases is not completely understood. While most studies suggest that inflammatory cells are major producers of this type of cytokine, damaged hepatocytes, activated HSC, and Kupffer cells are also able to secrete a number of pro-inflammatory chemokines. Therefore, a complex interplay between resident and infiltrating cells takes place during hepatic tissue repair. Platelets are another cell type that can release chemokines, such as CXCL4, also known as platelet factor 4 (PF4). This platelet-derived chemokine promotes monocyte arrest from rolling on the vascular wall and monocyte differentiation to macrophages [[4]Gleissner C.A. von Hundelshausen P. Ley K. Platelet chemokines in vascular disease.Artherioscler Thromb Vasc Biol. 2008; 28: 1920-1927Crossref PubMed Scopus (228) Google Scholar]. CXCL4 is also chemotactic for neutrophils and fibroblasts. It is stored in high micromolar concentrations in the alpha granules of platelets and is released upon their activation. An alternatively spliced variant of CXCR3, named CXCR3B, acts as a functional receptor for CXCL4 [[5]Lasagni L. Francalanci M. Annunziato F. Lazzeri E. Giannini S. Cosmi L. et al.An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as a functional receptor for platelet factor 4.J Exp Med. 2003; 197: 1537-1549Crossref PubMed Scopus (600) Google Scholar]. In the study by Moreno Zaldivar et al. [[6]Zaldivar M.M. Pauels K. von Hundelshausen P. Berres M.L. Schmitz P. Bornemann J. et al.Hepatology. 2010; 51: 1345-1353Crossref PubMed Scopus (123) Google Scholar], they provide evidence that CXCL4 is a platelet-derived factor that modulates experimentally induced liver fibrosis. In this work, the authors demonstrate that CXCL4 is up-regulated in liver with active fibrogenesis in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Importantly, the degree of expression is higher in patients with more advanced fibrosis. In mice with toxic-induced liver fibrosis, CXCL4 overexpression was associated with aggregation and activation of platelets, which accumulated in the vicinity of areas with collagen deposition. Although a direct release of CXCL4 by platelets was not demonstrated, their results suggest that these cells are a potential source of CXCL4 during hepatic tissue repair. The functional implication of CXCL4 in liver fibrosis was proven in CXCL4−/− mice, which displayed reduced inflammation and fibrosis after carbon tetrachloride administration. In particular, a reduced number of CD8+T cells were observed in CXCL4−/− mice, suggesting a role for this chemokine in lymphocyte activation and trafficking. At the cellular level, the authors provided convincing evidence that CXCL4 induces proliferation, chemotaxis, and chemokine expression in activated HSC, suggesting a direct role in the expansion of fibrogenic cells. The study by Moreno Zaldivar et al. has important physiopathological implications. First, it highlights the potential role of activated platelets in liver fibrogenesis. Platelets are among the first type of cells that are recruited in the areas of injury and are known to release powerful fibrogenic cytokines, such as transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) as well as serotonin in order to favour liver regeneration [7Lisman T. Porte R.J. The role of platelets in liver inflammation and regeneration.Semin Thromb Hemost. 2010; 36: 170-174Crossref PubMed Scopus (45) Google Scholar, 8Lesurtel M. Graf R. Aleil B. Walther D.J. Tian Y. Jochum W. et al.Platelet-derived serotonin mediates liver regeneration.Science. 2006; 312: 104-107Crossref PubMed Scopus (619) Google Scholar]. These actions indicate that platelet activation plays a role in the hepatic wound healing response to injury. The current study suggests that they may also participate in the exaggerated fibrogenic response of the liver after repeated injury. Because of the dual effect of platelets in promoting liver generation and fibrogenesis, further studies should investigate if the manipulation of platelet trafficking and/or activation has detrimental or beneficial effects in experimental models of acute and chronic liver injury. Second, CXCL4 promotes blood coagulation by moderating the effects of heparin-like molecules [[9]Visentin G.P. Ford S.E. Scott J.P. Aster R.H. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.J Clin Invest. 1994; 93: 81-88Crossref PubMed Scopus (549) Google Scholar]. The activation of the coagulation cascade is an important biological event during both moderate and severe liver injury [[10]Calvaruso V. Maimone S. Gatt A. Tuddenham E. Thursz M. Pinzani M. et al.Coagulation and fibrosis in chronic liver disease.Gut. 2008; 57: 1722-1727Crossref PubMed Scopus (66) Google Scholar]. It yields a number of activated proteases with powerful inflammatory properties and it can also modulate hepatic microcirculation leading to tissue hypoxia. This is a “hot” area in the field of liver fibrosis and it is under extensive investigation. New advances are anticipated in the coming years. And third, targeting CXCL4 appears to be an appealing new strategy to treat liver inflammation and fibrosis. However, due to the diversity of the biological actions of CXCL4 in modulating immunity and coagulation, extensive experimental studies should first evaluate both the beneficial and adverse effects of drugs interfering CXCL4 in chronic liver injury. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.