API

Relationship: 1778

Title

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Leukocyte recruitment/activation leads to Activation, Stellate cells

Upstream event

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Leukocyte recruitment/activation

Downstream event

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Activation, Stellate cells

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Endocytic lysosomal uptake leading to liver fibrosis adjacent High

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens NCBI
mouse Mus musculus NCBI
rat Rattus norvegicus NCBI

Sex Applicability

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Sex Evidence
Unspecific

Life Stage Applicability

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Term Evidence
All life stages

Key Event Relationship Description

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During hepatic injury quiescent hepatic stellate cells (HSCs) undergo activation which is associated with proliferation, increased contractile activity, fibrogenesis, changes in matrix protease activity, loss of intracellular retinoid storage, production of cytokines, and phenotypic transformation (Friedmann, 2000).

Different inflammatory cells activate HSCs to secrete collagen (Casini et al., 1997). Factors that promote activation of HSC include the cytokines, TNF-α and TGF-β (Bachem et al., 1993), endothelin-l (ET-1) (Rockey and Chung, 1996) and oxidative stress (Lee et al., 1995).

TGF-β is considered the most powerful mediator of HSC activation in vitro and in vivo (Friedmann, 2000; Bataller and Brenner, 2005). TGF-β triggers phenotypical HSC activation by paracrine and autocrine action, and induces collagen I expression and α-smooth muscle actin (α-SMA) stress fiber organization (Gressner et al., 2002; Dooley et al., 2003). TGF-β binds to heteromeric transmembrane receptors, including TβRI and TβRII (Heldin et al., 1997). Binding to TβRII triggers heteromerization with and transphosphorylation of TβRI. The signal is then propagated through phosphorylation of receptor associated Smad2 and Smad3 and their oligomerization with the common mediator Smad4. Complexes of phosphorylated Smad2 or 3 and Smad4 translocate into the nucleus, where they modulate the transcription of target genes, including those encoding extracellular matrix components (ECM) components (Piek et al., 1999; Miyazono et al., 2000; Moustakas et al., 2001). IFN-γ suppresses TGF-β and PDGF-dependent signalling pathways (Fujita et al., 2006).

IL-33 is released by stressed hepatocytes and attracts type 2 innate lymphoid cells (ILC2), which trigger the profibrogenic activation of HSCs via mediators such as IL-13 (McHedlidze et al., 2013; Heymann and Tacke, 2016). The binding of IL-33 to ST2 receptor activates NF-kB and mitogen activated protein kinases (MAPKs) and drives the production of pro-inflammatory and Th2 associated cytokines (Schmitz et al., 2005), which resulted in the stimulation of α-SMA and collagen expression in HSCs (Tan et al., 2018).

IL-13 indirectly activates TGF-β by upregulating the expression of matrix metalloproteinases (MMPs) that cleave the LAP–TGF-β1 complex (Lee et al., 2001; Lanone et al., 2002). Also, IL-13 has been reported to directly induce production of TGF-β1 in HSCs during liver fibrosis (Shimamura et al., 2008). When treating HSCs with IL-13 and performing a time-course analysis, a time-dependent activation of Smad proteins was observed (Liu et al., 2011).

TNF-α stimulated both p38 MAPK and JNK activity in a time-dependent manner, same as ET-1. However, TGF-β had no significant stimulatory effect on either of these MAPKs. The addition of p38 MAPK inhibitor pyridinyl imidazole derivative SB202190 resulted in reduction of α-SMA, indicator of activated HSC (Reeves et al., 2000)

Oxidative stress enhanced activation of HSCs and collagen synthesis in them, whereas antioxidants stopped the stimulatory effect of free radicals (Lee et al., 1995; Svegliati-Baroni et al., 2001). Oxidative stress molecules, such as superoxide, hydrogen peroxide, hydroxyl radicals, may be derived from hepatocytes, activated KCs, other inflammatory cells and HSCs (Natarajan et al., 2006; Kisseleva and Brenner, 2007; Lee and Friedman, 2011).

Liver-infiltrating CD14+ CD16+ monocytes secrete high levels of chemokines (such as CCL1, CCL2, CCL3, CCL5), cytokines (IL-1α, IL-1β, IL-6, IL-13, IL-16, TNF-α and macrophage migration inhibitory factor), growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor) and can efficiently activate primary HSC in vitro (Liaskou et al., 2013; Zimmermann et al., 2010).

Neutrophils may activate HSCs through matrix degradation, secreting compounds like elastase, which then degrades laminin, an extracellular matrix protein in normal liver that is critical for keeping stellate cells in a quiescent state (Friedman et al., 1989). Neutrophil-derived reactive oxygen species (ROS) significantly stimulated procollagen type I accumulation in the HSC culture medium, while the addition of vitamin E or SOD impaired the ROS stimulated stimulation of procollagen I (Casini et al., 1997).

Macrophages are primary source of TGF-β1 in the fibrotic liver (Bataller and Brenner, 2009). Macrophages release several pro-inflammatory cytokines like TNF-α or IL-1 (Tacke and Zimmermann, 2014), which activate the transcription factor NF-kB in HSC and promote the survival of activated HSC (Pradere et al., 2013).

Kupffer cells, liver resident macrophages, after their activation, activate HSC via mechanisms that involve the potent profibrotic cytokines like TGF-β and platelet derived growth factor (PDGF), and ROS (Karlmark et al., 2008; Bataller and Brenner, 2009; Bataller and Lemon, 2012). Apart from directly stimulating matrix-secreting HSC, hepatic macrophages may aggravate scarring by promoting HSC survival via IL-1 and TNF-α induced NF-kB activation (Pradere et al., 2013).  Beside resident macrophages, infiltration of macrophages from blood is essential for liver fibrogenesis (Duffield et al., 2005; Imamura et al., 2005).

Th2 cell– derived cytokines, IL-4, IL-5, IL-13, can enhance fibrosis progression by stimulating TGF-β production in macrophages and by direct effects on HSCs (Wynn, 2004).

DCs have a minor contribution to NF-kB activation (Pradere et al., 2013).

NKT cells were also found to promote liver fibrogenesis in vivo, likely by releasing pro-inflammatory cytokines and activating HSCs (Wehr et al., 2013; Syn et al., 2012). However, there are also studies demonstrating that NKT cells may exert antifibrotic actions, because they can, under certain conditions, also kill HSC and produce IFN-γ, like NK cells (Gao et al., 2013; Park et al., 2009).

Signalling pathways for HSC activation include, for example, NF-kB that is involved in HSC activation upon lipopolysaccharide (LPS) or TLR4 stimulation or ATP induced cytosolic Ca2+ influx via purinergic signalling receptors (Dranoff et al., 2004). The activation of TLR4 receptor in HSC downregulates TGF-β pseudoreceptor BAMBI and sensitizes these cells for TGF-β, resulting in increased ECM production by HSCs and fibrosis (Seki et al., 2007).

Activated HSCs secrete inflammatory chemokines, express cell adhesion molecules, and modulate the activation of lymphocytes (Vinas et al., 2003). Therefore, a vicious circle in which inflammatory and fibrogenic cells stimulate each other is likely to occur (Maher, 2001).

Evidence Supporting this KER

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Biological Plausibility

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The recruitment of immune cells from the circulation into the injured tissue is the key mechanism during fibrogenesis in the liver (Heymann and Tacke, 2016).

Empirical Evidence

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Upon stimulation, Th1 cells produce interferon-gamma, which is antifibrogenic in liver. C57BL/6 mice contain primarily Th1 cells. Thus, the weak response to CCl4 in these mice is consistent with an interferon effect. In contrast, BALB/c mice have primarily Th2 lymphocytes. Th2 cells produce IL-4, which induces TGF-β. Both of these cytokines are profibrogenic in liver, which explains why BALB/c mice display enhanced fibrosis in response to CCl4 in comparison with C57BL/6 mice (Maher, 1999).

In vivo data from Karlmark et al., 2009 suggested that intrahepatic CD11bF4/80 monocyte-derived cells, same as liver resident macrophages, produce TGF-β1 and thereby directly activate HSCs. This was confirmed in an in vitro experiment, in which only intrahepatic recruited monocytes could readily activate HSCs in a TGF-β–dependent manner.

There is strong evidence that the blockade of TGF-β alone is sufficient to completely block experimental fibrogenesis in liver (reviwed in Gressner et al., 2002).

Overexpression of Smad7, a natural antagonist of TGF-β signalling, prevents activation of HSCs and liver fibrosis in rats (Dooley et al., 2003).  

The activation of HSC by CD14 + CD16+ monocytes could be partially blocked by anti- TGF-β antibodies (Zimmermann et al., 2010).

In rats receiving CCl4, HSC activation correlates temporally and spatially with superoxide production (Montosi et al., 1998).

Macrophage depletion by administration of diphtheria toxin intraperitoneally or intravenous led to a significant reduction in the number of HSCs (Duffield et al., 2005).

After bile duct ligation, Kupffer cell–depleted mice showed almost complete suppression of HSC activation and fibrosis (Seki et al., 2007).

Liver injury caused by ischemia and reperfusion, along with TNF-α, CXCL1, and endothelin-A receptor expression, was significantly decreased in HSC-depleted mice compared with controls, with decreased neutrophil infiltration and parenchymal cell death. This suggests that HSCs are involved in hepatic production of CXCL1 and contribute to neutrophil recruitment (Stewart et al., 2014).

Important evidence that HSCs produce chemoattractant is that MCP-1 mRNA was clearly co-distributed with cells expressing α-SMA, a marker of activated HSCs (Marra et al., 1998).

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Even though many studies claim that TGF-β is the major activating factor for HSCs, one study showed that TGF-β is not an activating factor for HSC, but that more likely it is required for the activated HSCs to survive (Imamura et al., 2005).

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Human (Zimmermann et al., 2010; Liaskou et al., 2013)

Mouse (Seki et al., 2007; Gäbele et al., 2009; Pradere et al., 2013; McHedlidze et al., 2014)

Rat (Reeves et al., 2000;  Duffield et al., 2005; Imamura et al., 2005)

References

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Bachem MG, Sell KM, Melchior R, Kropf J, Eller T, Gressner AM. Tumor necrosis factor alpha (TNFa) and transforming growth factor pl (TGF/31) stimulate fibronectin synthesis and the transdifferentiation of fat-storing cells in the rat liver into myofibroblasts. Virchows Archiv B Cell Path (1993) 63: 123-30.

Bataller R, Brenner DA. Liver fibrosis. J Clin Invest (2005) 115:209-218.

Bataller R, Lemon SM. Fueling fibrosis in chronic hepatitis C. Proc Natl Acad Sci U S A. (2012) 109:14293–4.

Casini A, Ceni E, Salzano R, Biondi P, Parola M, Galli A, Foschi M, Caligiuri A, Pinzani M, Surrenti C. Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide. Hepatology. (1997) 25:361–367.

Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, Ten Dijke P, Gressner AM. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology (2003) 125: 178–191.

Dranoff JA, Ogawa M, Kruglov EA, Gaça MD, Sévigny J, Robson SC, Wells RG. Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol (2004) 287:G417-24.

Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest (2005) 115:56-65.

Friedman SL, Roll FJ, Boyles J, Arenson DM, Bissell D. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem (1989) 264:10756-10762.

Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem (2000) 275:2247-2250.

Fujita T, Maesawa C, Oikawa K, Nitta H, Wakabayashi G, Masuda T. Interferon-gamma down regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats. Int J Mol Med (2006) 17:605-16.

Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta (2013) 1832:1061-9.

Gäbele E, Froh M, Arteel GE, Uesugi T, Hellerbrand C, Schölmerich J, Brenner DA, Thurman RG, Rippeb RA. TNFalpha is required for cholestasis-induced liver fibrosis in the mouse. Biochem Biophys Res Commun. (2008) 378(3):348-53.

Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-β in hepatic fibrosis. Front. Biosci. (2002) 7: d793–807.

Heldin CH, Miyazono K, ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature (1997) 390:465-471.

Heymann F, Tacke F. Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol (2016) 13: 88–110.

Imamura M, Ogawa T, Sasaguri Y, Chayama K, Ueno H. Suppression of macrophage infiltration inhibits activation of hepatic stellate cells and liver fibrogenesis in rats. Gastroenterology (2005) 128:138-146.

Karlmark KR, Wasmuth HE, Trautwein C, Tacke F. Chemokine-directed immune cell infiltration in acute and chronic liver disease. Expert Rev Gastroenterol Hepatol (2008) 2:233-242.

Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology (2009) 50:261-74.

Kisseleva T, Brenner DA. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J Gastroenterol Hepatol (2007) 22(Suppl 1):S73–S78.

Lanone S, Zheng T, Zhu Z, Liu W, Lee CG, Ma B, Chen Q, Homer RJ, Wang J, Rabach LA, Rabach ME, Shipley JM, Shapiro SD, Senior RM, Elias JA. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling. J. Clin. Invest (2002) 110:463–474.

Lee KS, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest (1995) 96: 2461-8.

Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, KOteliansky V, Shipley M, Gotwals P, Noble P, Chen Q, Senior RM, Eliasa JA. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. (2001) 194(6):809-21.

Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol (2011) 25:195–206.

Liaskou E, Zimmermann HW, Li KK, Oo YH, Suresh S, Stamataki Z, Qureshi O, Lalor PF, Shaw J, Syn WK, Curbishley SM, Adams DH. Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics. Hepatology (2013) 57:385-98.

Liu Y, Meyer C, Müller A, Herweck F, Li Q, Müllenbach R, Mertens PR, Dooley S, Weng HL. IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-β-independent Smad signaling. J Immunol. (2011) 187(5): 2814–2823.

Maher JJ. Leukocytes as modulators of stellate cell activation.  Alcohol Clin Exp Res. (1999) 23(5): 917–921.

Maher JJ. Interactions between hepatic stellate cells and the immune system. Semin. Liver Dis. (2001) 21:417–426.

Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration.  Am J Pathol. (1998) 152(2): 423–430.

McHedlidze T, Waldner M, Zopf S, Walker J, Rankin AL, Schuchmann M, Voehringer D, McKenzie AN, Neurath MF, Pflanz S, Wirtz S. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity  (2013) 39: 357–371.

Miyazono K, ten Dijke P,  Heldin CH. TGF-β signalling by Smad proteins. Adv Immunol (2000) 75:115-157.

Montosi G, Garuti C, Iannone A, Pietrangelo A. Spatial and temporal dynamics of hepatic stellate cell activation during oxidant-stress-induced fibrogenesis. Am J Pathol (1998) 152: 1319-1326.

Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J. Cell Sci. (2001) 114: 4359–4369.

Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, Balasubramanian KA. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models.  J Gastroenterol Hepatol.  (2006) 21(6): 947–957.

Park O, Jeong WI, Wang L, Wang H, Lian ZX, Gershwin ME, Gao B. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology (2009) 49:1683 94.

Piek E, Heldin CH,  ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J (1999) 13:2105-2124.

Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, Jang MK, Guenther ND, Mederacke I, Friedman R, Dragomir AC, Aloman C, Schwabe RF. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology (2013) 58:1461–1473.

Reeves HL, Dack CL, Peak M, Burt AD, Day CP. Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture. J Hepatol.  (2000), 32: 465-472.

Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis: implications for endothelin in the pathogenesis of wound healing. J Clin Invest (1996) 98: 1381-8.

Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity (2005) 23: 479–490.

Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. (2007) 13:1324–32.

Shimamura T, Fujisawa T, Husain SR, Kioi M, Nakajima A, Puri RK. Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model. J. Immunol. (2008) 181: 4656–4665.

Stewart RK, Dangi A, Huang C, Murase N, Kimura S, Stolz DB, Wilson GC, Lentsch AB, Gandhi CR. A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury. J Hepatol.  (2014) 60:298–305.

Svegliati-Baroni G, Saccomanno S, van Goor H, Jansen P, Benedetti A, Moshage H. Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells. Liver (2001) 21, 1-12.

Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira Tde A, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM. NKT associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut (2012) 61:1323-9.

Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol (2014) 60:1090-6.

Tan Z, Liu Q, Jiang R, Lv L, Shoto SS, Maillet I,  Quesniaux V, Tang J, Zhang W, Sun B, Ryffel B. Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells. Cell Mol Immunol (2018) 15(4): 388–398.

Vinas O, Bataller R, Sancho-Bru P, Ginès P, Berenguer C, Enrich C, Nicolás JM, Ercilla G, Gallart T, Vives J, Arroyo V, Rodés J. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology. (2003) 38:919–929.

Wehr A, Baeck C, Heymann F, Niemietz PM, Hammerich L, Martin C, Zimmermann HW, Pack O, Gassler N, Hittatiya K, Ludwig A, Luedde T, Trautwein C, Tacke F. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. J Immunol (2013) 190:5226-36.

Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol (2004) 4:583-594.

Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, Tischendorf JJ, Luedde T, Weiskirchen R, Trautwein C, Tacke F. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One (2010) 5:e11049.