Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activation

Hong, Feng; Tuyama, Ana C.; Lee, Ting-Fang; Loke, Johnny; Agarwal, Ritu; Cheng, Xin; Garg, A.; Fiel, M. Isabel; Schwartz, Myron; Walewski, José L.; Branch, Andrea D.; Schecter, Alison D.; Bansal, Meena B.

doi:10.1002/hep.22890

Cited by 137 publications

(157 citation statements)

References 29 publications

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“…However, our study also indicates that sCD74 inhibits the MIF/CXCR4 axis and thus induces a molecular switch from MIF‐mediated prosurvival signaling through CXCR4/AKT (profibrotic) to cell death induction by CD74 (antifibrotic). Our findings are consistent with previous studies showing that CD74 mediates antifibrotic properties whereas CXCR4 promotes profibrotic effects 26, 71…”

Section: Discussionsupporting

confidence: 94%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Discussionsupporting

confidence: 94%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Human LX-2, hTERT, and FH11 hepatic stellate cell lines LX-2 [33] and hTERT cells [34] are immortalized activated human HSCs cell lines, while FH11 cells [35] are primary activated human HSC isolated from liver explants. The expression of adenosine receptors on HSC cell lines varied considerably (as seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

Expression of mediators of purinergic signaling in human liver cell lines

Goree

Lavoie

Fausther

et al. 2014

Purinergic Signalling

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Purinergic signaling regulates a diverse and biologically relevant group of processes in the liver. However, progress of research into functions regulated by purinergic signals in the liver has been hampered by the complexity of systems probed. Specifically, there are multiple liver cell subpopulations relevant to hepatic functions, and many of these have been effectively modeled in human cell lines. Furthermore, there are more than 20 genes relevant to purinergic signaling, each of which has distinct functions. Hence, we felt the need to categorize genes relevant to purinergic signaling in the best characterized human cell line models of liver cell subpopulations. Therefore, we investigated the expression of adenosine receptor, P2X receptor, P2Y receptor, and ecto-nucleotidase genes via RT-PCR in the following cell lines: LX-2, hTERT, FH11, HepG2, Huh7, H69, and MzChA-1. We believe that our findings will provide an excellent resource to investigators seeking to define functions of purinergic signals in liver physiology and liver disease pathogenesis.

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“…5E). Finally, the chemokine receptor CXCR4 and its ligand CXCL12/SDF1a, which were recently implicated in HSC activation, 24 were significantly down-regulated by IFNc-PEG-PPB (Fig. 5F), whereas IFNc and IFNc-PEG had no effect.…”

Section: Resolution Of Liver Fibrosis By Ifnc-peg-ppb Inmentioning

confidence: 96%

Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

et al. 2011

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Liver fibrogenesis is a process tightly controlled by endogenous anti-and pro-fibrogenic factors. Interferon gamma (IFNc) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNc receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNc specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNc to a cyclic peptide recognizing the plateletderived growth factor beta receptor (PDGFbR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNc conjugates were analyzed in vitro for PDGFbR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachlorideinduced liver fibrosis in mice. The targeted-IFNc construct showed PDGFbR-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFNc construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNc was ineffective in both models. Moreover, in contrast to unmodified IFNc, our engineered targeted-IFNc did not induce IFNc-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. Conclusion: This study presents a novel HSC-targeted engineered-IFNc, which in contrast to systemic IFNc, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. (HEPATOLOGY 2011;54:586-596)

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Hepatic stellate cells express functional CXCR4: Role in stromal cell-derived factor-1α-mediated stellate cell activation

Cited by 137 publications

References 29 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Expression of mediators of purinergic signaling in human liver cell lines

Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

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