Reply to: “Depletion of hepatic stellate cells: Have Kupffer cells lost their bad neighbor?”
Authors: Anil Dangi, Chandrashekhar R. Gandhi
Journal: Journal of Hepatology (2014)

A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injuryJournal of HepatologyVol. 60Issue 2PreviewHepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver. Full-Text PDF Depletion of hepatic stellate cells: Have Kupffer cells lost their bad neighbor?Journal of HepatologyVol. 61Issue 3PreviewIn a recent issue of this journal, Stewart et al. [1] presented a major breakthrough in liver research models. The authors used transgenic mice expressing herpes simplex virus thymidine kinase (TK) under the glial fibrillary acidic protein (GFAP) promoter. Proliferation of hepatic stellate cells (HSC) was first induced by CCl4 and then mice were treated with ganciclovir, which was metabolized by TK into toxic nucleotide analogues, ultimately leading to HSC death (≈70% depletion). Afterwards, mice were subjected to ischemia/reperfusion and to endotoxin treatments. Full-Text PDF Open Access We appreciate the insightful commentary by Marcos on our recently published manuscript [[1]Stewart R.K. Dangi A. Huang C. Murase N. Kimura S. Stolz D.B. et al.A novel method of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.J Hepatol. 2014; 60: 298-305Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar], where they suggest that the loss of communication between hepatic stellate cells (HSCs) and closely associated Kupffer cells can be an important mechanism of the amelioration of ischemia/reperfusion (I/R)- or LPS-induced injury in HSC-depleted liver. We agree with this view since Kupffer cells have been shown to elicit inflammatory response, and their blockade or elimination ameliorates hepatic injury in several animal models [[2]Gandhi C.R. Kupffer cells.in: Molecular pathology of liver diseases. Springer, 2010: 81-96Google Scholar]. The role of Kupffer cells in mediating HSC activation and activation-dependent fibrogenic activity through mediators including free radicals, TNF-α and TGF-β is well documented [[3]Friedman S.L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev. 2008; 88: 125-172Crossref PubMed Scopus (2220) Google Scholar]. However, little is known about the influence of HSCs on Kupffer cells in physiology and pathology. Thus based on the observations of our report, the view that juxtacrine (physical contact) and paracrine (via soluble mediators) interactions between these two cell types, due to their close proximity, regulate physiologic and pathophysiologic processes in the liver is a rational assessment. The interactions between Kupffer cells and HSCs, however, must be considered to be very complex due to heterogeneity in the individual cell populations. Evidence suggests that the M1 Kupffer cells play a key role in inflammatory diseases whereas M2 Kupffer cells promote resolution of inflammation and tissue injury [[4]Kinoshita M. Uchida T. Sato A. Nakashima M. Nakashima H. Shono S. et al.Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice.J Hepatol. 2010; 53: 903-910Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar]. Furthermore, heterogeneity in Kupffer cells is also demonstrated with their differential phagocytic activity and expression of biologically active mediators in periportal vs. pericentral regions [5Sleyster E.C. Knook D.L. Relation between localization and function of rat liver Kupffer cells.Lab Invest. 1982; 47: 484-490PubMed Google Scholar, 6Hoedemakers R.M. Morselt H.W. Scherphof G.L. Daemen T. Heterogeneity in secretory response of rat liver macrophages of different size.Liver. 1995; 15: 313-319Crossref PubMed Scopus (19) Google Scholar]. Similarly, heterogeneity between periportal and pericentral HSCs has also been illustrated [[7]Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.Semin Liver Dis. 2001; 21: 311-335Crossref PubMed Scopus (627) Google Scholar]. Nevertheless, our results [[1]Stewart R.K. Dangi A. Huang C. Murase N. Kimura S. Stolz D.B. et al.A novel method of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.J Hepatol. 2014; 60: 298-305Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar] indicate that HSCs elicit pro-inflammatory response in Kupffer cells based on the reduced expression of TNF-α and CXCL1, and increased or unaltered expression of IL-6 in stellate cell-depleted mice after I/R or LPS challenge. We also observed a modest increase in anti-inflammatory cytokine IL-10 expression in HSC-depleted compared with control liver in both models of hepatic injury (unpublished finding). Since HSCs themselves produce all of these mediators [8Sumpter T. Dangi A. Matta B. Huang C. Stolz D. Vodovotz Y. et al.Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO.J Immunol. 2012; 189: 3848-3858Crossref PubMed Scopus (53) Google Scholar, 9Dangi A. Sumpter T. Kimura S. Stolz D.B. Murase N. Raimondi G. et al.Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance.J Immunol. 2012; 188: 3667-3677Crossref PubMed Scopus (66) Google Scholar], their interactions with Kupffer cells become even more interesting and important in hepatic inflammation and injury. The property of HSCs to influence the characteristics of other cell types may not be limited only to Kupffer cells. For example, greater increase in endothelin-1 expression upon LPS challenge of HSC-depleted liver compared to the control liver [[1]Stewart R.K. Dangi A. Huang C. Murase N. Kimura S. Stolz D.B. et al.A novel method of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.J Hepatol. 2014; 60: 298-305Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar] indicates their regulation of hepatic endothelial cells, the primary cell type to produce this vasoconstrictor peptide [[10]Gandhi C.R. Berkowitz D.E. Watkins W.D. Endothelins: biochemistry and pathophysiologic actions.Anesthesiology. 1994; 80: 892-905Crossref PubMed Scopus (61) Google Scholar]. Furthermore, HSCs were shown to induce tolerogenicity in myeloid dendritic cells and increase immunosuppressive potential of regulatory T cells via physical contact, and these interactions were also found to alter pro- and anti-inflammatory cytokine production by either cell type [8Sumpter T. Dangi A. Matta B. Huang C. Stolz D. Vodovotz Y. et al.Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO.J Immunol. 2012; 189: 3848-3858Crossref PubMed Scopus (53) Google Scholar, 9Dangi A. Sumpter T. Kimura S. Stolz D.B. Murase N. Raimondi G. et al.Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance.J Immunol. 2012; 188: 3667-3677Crossref PubMed Scopus (66) Google Scholar]. We, however, note that in our study both Kupffer cells and HSCs should be considered quiescent when the mice were subjected to I/R or endotoxin challenge [[1]Stewart R.K. Dangi A. Huang C. Murase N. Kimura S. Stolz D.B. et al.A novel method of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury.J Hepatol. 2014; 60: 298-305Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar]. Although we do not exclude the possibility that HSC depletion may already have altered Kupffer cell characteristics, the mode of interactions between them is expected to be quite different with their activation during progression of chronic liver injury. Thus, the hypothesis that depletion of HSCs drives Kupffer cells to less inflammatory phenotype (M1 to M2 switch) proposed by Marcos and Lopez will be an interesting area for future investigation both in acute and chronic liver injury. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.