Autoimmunity Reviews 14 (2015) 293–303

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Autoimmunity Reviews

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Review Hepatocyte growth factor: A regulator of inflammation and autoimmunity

Nicolas Molnarfi a,b,1, Mahdia Benkhoucha a,b,1, Hiroshi Funakoshi d, Toshikazu Nakamura e, Patrice H. Lalive a,b,c,⁎ a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland b Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva, Geneva, Switzerland c Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, University Hospital of Geneva, Geneva, Switzerland d Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan e Neurogen Inc., Nakahozumi, Ibaraki, Osaka, Japan article info abstract

Article history: Hepatocyte growth factor (HGF) is a pleiotropic cytokine that has been extensively studied over several decades, Received 20 November 2014 but was only recently recognized as a key player in mediating protection of many types of inflammatory and au- Accepted 25 November 2014 toimmune diseases. HGF was reported to prevent and attenuate disease progression by influencing multiple Available online 1 December 2014 pathophysiological processes involved in inflammatory and immune response, including cell migration, matura- tion, cytokine production, antigen presentation, and T cell effector function. In this review, we discuss the actions Keywords: fl HGF and mechanisms of HGF in in ammation and immunity and the therapeutic potential of this factor for the treat- fl c-Met ment of in ammatory and autoimmune diseases. Inflammation © 2014 Elsevier B.V. All rights reserved. Autoimmunity Autoimmune regulator Therapy

Contents

1. Introduction...... 294 2. Hepatocytegrowthfactor(HGF)...... 294 2.1. StructuralandfunctionalcharacteristicsofHGF...... 294 2.2. HGFreceptor(c-Met)...... 294 3. RegulationandroleoftheHGF/c-Metaxisduringimmunereactions...... 294 3.1. Monocytesandmacrophages...... 295 3.2. Dendriticcells(DCs)...... 295 3.3. Tlymphocytes...... 296 3.4. Blymphocytes...... 296 3.5. Neutrophils...... 297 3.6. Naturalkillercells...... 297 4. Role of HGF in inflammatory-mediateddiseaseanimalmodels...... 297 4.1. Rheumatoidarthritis...... 297 4.2. Autoimmune neuroinflammation ...... 297 4.3. Graft-versus-hostdisease(GVHD)...... 297 4.4. Kidneydiseases ...... 298 4.5. Cardiacdiseases...... 298 4.6. Inflammatoryboweldisease(IBD)...... 298 4.7. Lungdisease...... 298

⁎ Corresponding author at: Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva University Hospital, Faculty of Medicine, Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel.: +41 22 372 83 18; fax: +41 22 372 83 82. E-mail address: [email protected] (P.H. Lalive). 1 These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.autrev.2014.11.013 1568-9972/© 2014 Elsevier B.V. All rights reserved. 294 N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303

4.8. Liverdisease...... 298 5. HGFastherapeuticagent...... 298 6. Concludingremarks...... 299 7. Futuredirections ...... 299 Take-homemessages...... 300 Acknowledgments...... 300 References...... 300

1. Introduction HGF has a high affinity for its receptor c-Met, but the activation of the HGF/c-Met signaling is dependent on the subsequent binding of the β- Hepatocyte growth factor (HGF), also called scatter factor, is a poly- chain [25]. In addition to the major transcript encoding HGF, alternative peptide growth factor that belongs to the plasminogen family. Based on splicing of the HGF primary transcript generates natural variants that biological and gene expression assays, HGF has been described as a retained the c-Met-binding ability and have partial agonistic and antag- pleiotropic factor that is primarily secreted by mesenchymal cells [1] onistic activities on the full-length HGF protein [26]. and that elicits motility, proliferation, morphogenesis and proliferation of epithelia expressing the HGF receptor c-Met [2–5]. The importance 2.2. HGF receptor (c-Met) of HGF in mesenchyme-directed epithelial growth during embryogene- sis and organ development was evidenced by the demonstration that All biological activities of the mature HGF are mediated via the high mice with conventional c-Met- or HGF-null mutations died in utero affinity cell-surface receptor c-Met, a product encoded by the c-Met due to defects in placenta, liver and muscle development [6–8].Thesub- proto-oncogene [27]. Like its ligand, this receptor is a disulfide-linked sequent development of tissue-specific knockout mice further evi- α–β heterodimer that originates from the proteolytic cleavage of a sin- denced a major role for the HGF/c-Met signaling pathway as an gle chain precursor. The c-Met receptor is expressed in the normal epi- essential factor for mature tissue survival, protection and regeneration, thelium of the majority of tissues where it is primarily located at the and of particular interest, in providing less susceptibility to fibrosis and intercellular junctions together with cell adhesion molecules such as chronic inflammation [9]. In recent years, our work and that of others E-cadherin [28]. The c-Met protein is composed of a single-pass trans- have further shown that HGF regulates acute and chronic inflammation membrane β-chain (145 kDa) and a completely extracellular α-chain in a variety of disease models, including collagen-induced arthritis, au- (50 kDa). The α-subunit and the amino-terminal region of the β- toimmune neuroinflammation, inflammatory bowel disease and airway subunit form the extracellular domain. The remainder of the β-chain inflammation. This suggests that HGF modulates central inflammatory spans the plasma membrane and harbors a cytoplasmic region with and immune events that are common to many diseases and organ sys- tyrosine kinase-containing activity. tems. We discuss here the mechanisms by which HGF suppresses in- The binding of HGF to c-Met induces the kinase catalytic activity of flammatory immune responses. the receptor, which triggers the transphosphorylation of the tyrosines (Tyr) 1234 and Tyr 1235 and the engagement of various signal transduc- ers. Because of the multitude of transducers, c-Met initiates a whole 2. Hepatocyte growth factor (HGF) spectrum of biological activities. The transducers either directly interact with c-Met, such as the growth factor receptor-bound protein 2 2.1. Structural and functional characteristics of HGF (GRB2) [29], the c-Src tyrosine kinase [29], the adaptor Src Homology (SHC) 2 domain [30], the p85 subunit of phosphatidylinositol 3-kinase In the early 1980s, HGF was identified as a hormone-like substance in (PI3K) [31], and the signal transducer and activator of transcription 3 the serum of partially hepatectomized rats, based on its ability to stimu- (STAT3) [32], or indirectly through the GRB2-associated binding protein late DNA synthesis in cultured hepatocytes [10,11]. Within a few years, it 1(Gab1)[33], such as the phospholipase C-γ (PLC-γ) [34]. In a compara- became however evident that HGF elicits multiple biological activities in ble manner to HGF, the related plasminogen family member HGF-like/ multiple cell types [12]. In addition to serve as a mitogen for hepatocytes, macrophage stimulating protein (MSP) has been shown to mediate its independent studies identified HGF as a potent epithelial mitogen [2,13], biological activities through a unique cell-surface receptor characterized growth factor [14], morphogen [4], as well as a chemoattractant for mo- as Ron (recepteur d'origine nantais), a tyrosine kinase receptor that toneurons [15] and a cytotoxic factor toward tumor cell lines [16].Dueto structurally resembles to c-Met and that exhibits analogous biological ac- the homology in amino acid sequence of HGF to factors of the clotting tivities on target cells [35]. While c-Met alone is able to mediate signal- and fibrinolysis cascades, such as prothrombin and plasminogen, HGF ing, it has also been shown that c-Met could form heterodimers with belongs to the family of plasminogen-related growth factors, which other cellular surface receptors to mediate distinct signaling events. To also comprises HGF-like/macrophage stimulating protein (HGFl/MSP) date, functional interactions have been reported to occur with Ezrin [17–19]. HGF does not appear, however, to have pro- or anti-coagulant [36], β4-integrin [37], CD44 [38], Fas-receptor [39], semaphorin- activities [3]. HGF is synthesized and secreted as an inactive single receptor [40] and E-cadherin [41]. Finally, substantial data indicate that chain precursor (pro-HGF) of 728 amino acids that is stored in the extra- c-Met could be shed from the cell surface under physiologic and patho- cellular matrix due to its high affinity for sulfate proteoglycans [20].The logic conditions. Shedding of c-Met decreases the levels of receptor mol- mature HGF molecule is a disulfide-linked α–β heterodimer consisting ecules at the plasma membrane and further generates a decoy moiety of a 69 kDa α-chain and a 34 kDa β-chain originating from the post- that binds both to HGF and cell-surface c-Met, inhibiting dimerization translational conversion of the inactive single-chain precursor [21] via and transactivation of the native c-Met receptor [42–47]. the actions of serine proteases, including HGF activator (HGFA) [3], matriptase [22] and hepsin [23]. The larger chain (residues 1–494) con- tains a typical signal peptide, cleaved during secretion, followed by five 3. Regulation and role of the HGF/c-Met axis during immune distinct domains: an N-terminal hairpin loop homologous to the activa- reactions tion peptide of plasminogen and four kringle (K) domains [24]. The smaller β-chain (residues 495–728) contains a substrate-processing re- In addition to exert multiple biological activities on various types of gion that resembles to a typical serine protease domain. The α-chain of epithelial and endothelial cells, the HGF/c-Met axis also acts on some N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303 295 mesenchyme-derived cells, and in particular, hematopoietic cells, HGF convertase, therefore augmenting the responsiveness of these supporting a role for this system in hematopoiesis [48–50] and immuni- cells to HGF [59]. In functional assays, HGF potently induced directional ty [51]. In vitro, HGF is constitutively secreted by stromal cells isolated migration and cytokine production, such as IL-4, IL-1β, macrophage from different primary (bone marrow, thymus) and secondary (spleen, colony-stimulating factor (M-CSF), and granulocyte–macrophage lymph node, tonsil) lymphoid organs [52–55], and was reported to be (GM)-CSF, in human monocytes [72]. Additional studies have shown modulated by the addition of cytokines such as interleukin (IL)-1 and that HGF stimulated the antigen presentation of adult blood human tumor necrosis factor (TNF). The observation that IL-1α,IL-1β,TNF monocytes [73] and that c-Met signaling has been linked to prolifera- and interferon (IFN)-γ are positive regulators of HGF expression sup- tion in classically activated M1 macrophages in inflammation [74].To- ports a role for HGF in regeneration of tissues following the occurrence gether with the observation that macrophages themselves could of inflammatory diseases [56]. Activated T cells could also modulate the produce HGF [75], these various studies collectively indicate on first constitutive secretion of HGF by fibroblast-like stromal cells from hand that monocyte/macrophage activation by HGF during inflamma- lymphoid tissues [52]. In contrast, anti-inflammatory molecules, such tion may further modulate their specific functions at the site of the in- as glucocorticoids [53,57], 1,25-dihydroxyvitamin D3 [58], and trans- flammatory reaction through an autocrine mechanism, resulting in forming growth factor (TGF)-β [53,57] were found to inhibit HGF pro- exacerbation of inflammation. Accumulating data on the other hand duction. Within the hematopoietic compartment, expression of c-Met however indicate a protective action of HGF. Production of HGF by alve- is limited to progenitor cells and their antigen-presenting progeny, in- olar macrophages was reported to support the repair and healing of the cluding B cells, monocytes/macrophages [59], and dendritic cells inflammatory lung damage in patients with pulmonary fibrosis [76] and (DCs) [60]. Expression of c-Met mRNA has been also identified in thy- in a murine model for bacterial pneumonia [77]. HGF gene therapy also mocytes, and HGF increases the generation of mature T cells in fetal thy- enhanced infiltration of monocyte-derived macrophages into the in- mus organ cultures [54].Thefinding that c-Met expression is induced by jured kidneys, a mechanism likely contributing to the renal tissue repair inflammatory cytokines has formed the basis for a crucial role for the and regeneration [78]. Moreover, using a model of acute inflammation HGF/c-Met system in inflammatory responses to tissue injury [61]. elicited by lipopolysaccharide (LPS) and bone marrow-derived macro- The importance of the HGF/c-Met signaling has been implied in mono- phages from macrophage-specific conditional c-Met gene knockout cyte–macrophage activation [59,62], B cell homing to lymphoid micro- mice, HGF was shown to limit the inflammatory response [79].HGF environment [55], and modulation of DC functions including was also shown to inhibit chronic inflammation in adipose tissue migration [63,64], deactivation [65] and immunoregulation [66–69]. through the inhibition of macrophage-mediated pro-inflammatory cy- As detailed here, these actions confer protective effects to HGF in vari- tokines and up-regulation of adiponectin in adipocytes [80]. Mechanis- ous prototypical animal models of inflammatory-mediated diseases tically, HGF was found to decrease pro-inflammatory cytokine IL-6 such as collagen-induced arthritis, autoimmune neuroinflammation, production, while increasing that of the anti-inflammatory cytokine and inflammatory bowel disease. These findings further suggest that IL-10 via suppression of glycogen kinase synthase (GSK)3-β,apowerful HGF can regulate central inflammatory events that are common to regulator of inflammatory signaling [79]. Other data further indicate many diseases and organ systems. Mechanistically, accumulating evi- that HGF induces human and murine monocytes to acquire an immuno- dence indicates that HGF may prevent nuclear factor (NF)-κB in these modulatory phenotype through the extracellular signal-regulated pro- models from exerting its inflammatory action [69,70]. In this review, tein kinase (ERK)1/2 pathway [81]. we discuss in detail how HGF and c-Met interact within the immune system to regulate immune cell functions (see also Fig. 1) and inflam- 3.2. Dendritic cells (DCs) matory immune-mediated diseases (see Table 1). Central to the reactivation of antigen-specific T cells is the pre- 3.1. Monocytes and macrophages sentation of processed antigens by DCs, a mechanism that necessi- tates the migration of activated DCs to lymphoid organs following Monocytes are a population of leukocytes that terminally differenti- antigen capture. In a mouse model of skin immunity, activated c- ate into macrophages and DCs. Accumulating evidence supports HGF as Met signaling-deficient skin DCs fail to reach the draining lymph a central regulator of monocyte–macrophage functions [59]. In activat- nodes, establishing this signaling as a critical determinant for the de- ed human monocytes, specifically under conditions resembling those tachment and emigration of DCs from tissue upon activation [64]. found in inflammation, c-Met was found to be up-regulated, enabling Similar results were reported for the emigration of cutaneous DCs these cells to be readily accessible to the functional effects of HGF [62, (Langerhans cell, LC) from the skin [63] or attraction of DCs within 71]. In addition to up-regulate c-Met expression, the activation of the thymus [82].TheimportanceofHGFininfluencing murine im- human monocytes by potent inflammatory mediators such as endotox- mune responses was further powered by studies indicating that in in and IL-1β was reported to trigger the activity of cell-associated pro- addition to control the migratory process of DCs, HGF could impair

Fig. 1. Functions of HGF in immune regulation. 296 N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303

Table 1 Therapeutic approaches with recombinant HGF in various inflammatory disease models.

Tissues and disease models Model for injury or diseases Observed therapeutic effects References

Rheumatoid arthritis Type II collagen-induced arthritis Inhibition of development of experimental arthritis Okunishi et al., J Immunol, 2007; Enhancement of Th2-type immune response 179:5504–5513. Autoimmune neuroinflammation MOG-induced experimental Inhibition of development of EAE Benkhoucha et al., J Immunol, 2014; Bai autoimmune encephalomyelitis (EAE) Suppression of the APC function of DCs. et al., Nat Neurosc, 2012; 15:862–879. Down-regulation of Ag-induced Th1- and Th17-type immune responses Autoimmune myocarditis Immunization with purified porcine Reduction of severe myocardial damage and Futamatsu et al., Circ Res, 2005; cardiac myosin appearance of multinucleated giant cells 196:823–830. Enhancement of Th2-type immune response Allergic airway Ag sensitization and allergic airway Attenuation of experimental allergic airway Okunishi et al., J Immunol, 2005; inflammation / asthma inflammation induced by Ag inhalation inflammation 175:4745–4753. Ito et al., Am J Respir Cell Suppression of the APC function of DCs. Mol Biol, 2005; 32:268–280. Down-regulation of Ag-induced Th1- and Th2-type immune responses Suppression of airway inflammation, collagen deposition, smooth muscle hyperplasia, and remodeling Reduction in Th2 cytokines and fibrogenic growth factors Lupus nephritis, autoimmune Chronic graft-versus-host Prevention of lupus nephritis Decreased Ag Kuroiwa et al., Arthritis Res Ther, 2006; 8: sialoadenitis, and cholangitis disease (GVHD) presentation by both DCs and B cells. Inhibition of R123. Th2 generation Ulcerative colitis 2,4,6-Trinitrobenzene sulfonic Attenuation of acute colitis Oh et al., Am J Physiol Gastrointest Liver acid-induced colitis in mice Suppression of Th1-related cytokines Physiol, 2005;288:G729–735. Inflammatory bowel disease (dextran Inhibition of both loss of body weight and Hanawa et al., J Gene Med, sulfate sodium in mice) shortening of colon length 2006;8:623–635. Reduction of expression of mRNAs for IFN-γ, IL-18, and TNF in the colon. Increased expression of mRNA for IL-10 2,4,6-Trinitrobenzene sulfonic Suppression of colonic ulcer coverage and large Numata et al., Inflamm Bowel Dis, 2005; acid-induced colitis in rats intestinal shortening 11: 55 Reduction of the inflammatory cell infiltrate Cardiac allograft vasculopathy Ischemia and transplantation Reduction of acute and chronic rejection of the Yamaura et al., Circulation, 2004; allograft by promoting allograft tolerance 110:1650–1657. Immunosuppression mediated by Tregs murine DC activation [65,70] or confer them with suppressive activ- could enhance the generation of mature T cells, these findings, although ities such as the capacity to favor regulatory T cells (Tregs) induction indirect, suggest that the HGF/c-Met axis is regulating T-cell develop- [68,69,83]. Notably, DC expression of program-death ligand 1 (PD-L1) ment in the thymus [54]. HGF was also proposed as one of the key and IL-27, potent signals for DC-mediated induction of Treg cells, was mediators of T-cell suppression by human bone marrow mesenchymal found to be up-regulated by HGF treatment [83]. Likewise, human DCs stem cells [90], and further reported to promote human memory T-cell differentiated in the presence of HGF were shown to adopt a proto- adhesion and migration [91]. Whether HGF contributes to these various lerogenic phenotype with increased ability to generate regulatory T cells effects directly is not clear as the presence of the receptor on T cells was [60,84], a property that might be exploited therapeutically in T cell- either not indicated or not detected [91]. While a direct suppressive ef- mediated immune disorders. Conceivably, HGF might impair immuno- fect on murine CD4+ T cell proinflammatory functions was previously genic DC function through induction of IL-10 release by DCs [60,69],acy- attributed to HGF [51], most, if not all studies, rather collectively indi- tokine known to exhibit inhibitory effects on DCs in an autocrine manner cate that HGF primarily affects the function of antigen-presenting [85]. DCs exposed to HGF further exhibit decreased IL-12p70 secretion, cells (APCs) [65,68]. In this regard, we recently showed that modula- CD40 expression, and reduced capacity to induce T-cell proliferation tion of DCs by HGF indirectly inhibits the effector functions of murine and differentiation toward pro-inflammatory T cells [60,68]. Mechanisti- CD8+ T cells [92]. Since very low levels of c-Met expression could be cally, HGF was shown to impair the immunostimulatory function of DCs sufficient to mediate the actions of HGF [93], a direct effect of HGF on via activation of the Bruton's tyrosine kinase (Btk) [69] and its down- T cell effector function cannot however be completely excluded. stream PI3K/AKT pathway [69], as well as through induction of glucocorticoid-induced leucine zipper (GILZ) synthesis [83], a potent 3.4. B lymphocytes blocker of NF-κB signaling [86,87]. Of specific interest, expression of GILZ is a common trait of tolerogenic DCs generated by IL-10, TGF-β1 The observation that HGF could enhance antibody production by and glucocorticoids [88,89].Altogether,thesefindings indicate that HGF whole murine splenocyte cultures led to the first, although indirect, ev- reproduces the mechanism of immune regulation induced by potent im- idence that HGF could modulate B cell immune functions [94].Inmice, munomodulatory agent and therefore that this factor has potential for the naive murine B cells express both c-Met and its ligand HGF, and HGF treatment of immune-dependent diseases. regulates autocrine mature B cell survival via a CD74/CD44/c-Met sig- naling complex at the surface of B cells [95]. Within the lymphoid mi- 3.3. T lymphocytes croenvironment, HGF/c-Met axis was proposed to act as a paracrine signal pathway regulating B cell-follicular DC (FDC) interaction [55, Little is known about the role of HGF/c-Met in the regulation of 96], where centroblasts express c-Met and FDCs express and secrete T cells. Expression analysis of c-Met in the mouse thymus revealed that HGF [55] and HGF activator (HGFA) [96]. On tonsil B cells, concurrent c-Met mRNA transcripts are expressed at higher levels in the thymus CD40 and BCR ligation induces up-regulation of c-Met expression [55], during early ontogenesis than in adult thymus [54]. Together with the and stimulation with HGF leads to enhanced integrin-dependent adhe- observation that addition of exogenous HGF to thymus organ cultures sion of c-Met-expressing B cells to VCAM-1 expressed by FDCs [52,55, N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303 297

97]. In humans, naive and memory tonsillar B cells, as well as peripheral 4.1. Rheumatoid arthritis B cells do not express c-Met [55,96,97] and HGF [96], whereas germinal center (GC) tonsillar activated B cells and plasma cells exhibit c-Met ex- Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune pression. Consistent with c-Met and HGFA expression by plasma cells, disease that affects synovial joints. Elevated HGF serum levels were mea- data further indicate that HGF can serve as a potent growth and survival sured in RA patients in comparison with healthy subjects [105–107],sug- factor for malignant plasma cells, but also for normal plasma cells [96]. gesting a possible role of HGF in disease. The possible cell sources of HGF These findings demonstrate that induction of c-Met in vivo occurs in in RA have not been yet fully determined. Immunohistochemical staining GC B precursors, i.e., B cells that have been recently activated by antigen performed on synovial tissue specimens from RA patients revealed that and cognate T cells in the T-cell-rich extrafollicular areas. Overall, these c-Met is strongly expressed in fibroblasts, macrophages, endothelial studies indicate that the HGF/c-Met signaling contributes to T cell- cells, and synovial lining cells while HGF was found expressed only faint- dependent B cell differentiation, where HGF provided by FDCs helps to ly in macrophages and fibroblasts, and not at all in the endothelial cells of regulate B cell growth, survival, adhesion, and interactions with stromal synovial tissue [108–110].Becauseproinflammatory cytokines promote cells within the lymphoid microenvironment [52,55,96]. expression of HGF in several cell types, increased HGF expression in RA may possibly reflect the degree of inflammation rather than contributing to joint damage. In this context, HGF was reported to exert potent anti- 3.5. Neutrophils inflammatory effects on human chondrocytes through inhibition of NF- κB transactivating activity [111]. In collagen-induced arthritis, systemic HGF was reported to prime neutrophil oxidative response [98] and to delivery of HGF potently suppresses DC function and IL-17 secretion trigger polymorphonuclear neutrophil (PMN) transmigration to sites of from activated CD4+ T cells, and thus attenuates the incidence and se- acute inflammation through rapid activation of lymphocyte function- verity of autoimmune arthritis [67]. HGF was further found to promote associated antigen-1 (LFA-1) [99]. Direct imaging assays in zebrafish em- the development of IL-10-producing T cells and Th2-type immune re- bryos recently confirmed an important role for the HGF/c-Met signaling sponses through increased IL-10 production by DCs during the chronic cascade in the migration of neutrophil cells in vivo during immune re- inflammatory stage of experimental arthritis [67]. These data suggest sponse to wounding without protective effect on the inflammatory re- that HGF could be an attractive strategy for treating RA patients. sponse [100]. Interestingly, infiltrating PMNs into damaged tissues may further modulate local wound healing and repair through the release of 4.2. Autoimmune neuroinflammation HGF, a major mediator of tissue regeneration. Human PMNs were found to contain mobilizable intracellular pools of HGF [101],andstimu- Multiple sclerosis (MS) is a demyelinating inflammatory disorder of lation of human neutrophils with pro-inflammatory mediators such as the central nervous system (CNS), which involves autoimmune responses TNF, LPS or bacterial peptides (fMLP) increases the release of mature to myelin antigens. Studies in experimental autoimmune encephalomy- (bioactive) HGF from pre-constituted intracellular stores [102]. Data elitis (EAE), an animal model for MS and a prototype for autoimmune dis- from patients with systemic inflammatory response syndrome (SIRS) eases in general, indicate that HGF/c-Met signaling plays an important further support that increased HGF granule content and enhanced role in the regulation of autoimmune neuroinflammation. Seminal data degranulation of HGF by infiltrating neutrophils into the inflammatory in this animal model showed that TGF-β and IFN-β, contrary to IFN-γ tissue may play an important role in wound healing and organ regener- and TNF, can induce microglia to produce HGF within EAE demyelinated ation under those conditions [103]. lesions [189]. Within MS-like inflammatory lesions, c-Met is primarily expressed by macrophages and also a small population of DCs and c- Met is activated [74]. Severity of neuroinflammation and demyelination 3.6. Natural killer cells was found to be significantly reduced in transgenic EAE mice overex- pressing HGF in a neuron-specificmannerorinEAEmicereceivinganex- Only few studies have investigated the potential role of HGF on nat- ogenous supply of HGF [68,83,112]. Amelioration of autoimmune ural killer (NK) cell functions. Expression of c-Met mRNA was found in neuroinflammation was tightly associated with the capacity of HGF to various human NK cell lines. These “only at the RT-PCR level” data led to alter the balance of pro- (Th1, Th17) and anti-inflammatory (Th2 and the hypothesis that NK cells may represent target cells of HGF. In vivo Tregs) CD4+ T cells in both peripheral immune compartments and within administration of HGF in rats, in doses known to produce hepatotrophic the CNS by influencing DC function [68,83]. HGF limits EAE via expression activity, was shown to reduce NK cell cytotoxic activities [104].Invitro in DCs of GILZ, a key endogenous regulator of the inflammatory response assays however showed that HGF did not change spontaneous NK, [83]. HGF was also shown via DC deactivation to attenuate the effector ac- lymphocyte-activated killer, and antibody-dependent cellular cytotox- tivity of CD8+ cytotoxic T-cells, a population of T lymphocytes suspected icity cytolytic functions or redirected killing [104]. Collectively, these to contribute to neuronal dysfunction and degeneration in a variety of in- data indicate that HGF regulates NK cell cytotoxic activities through flammatory CNS disorders [92]. Collectively, these results raise the possi- some as-yet-unknown intermediary mechanism. bility that HGF may provide novel therapeutic opportunities for the treatment of immune T cell-mediated demyelinating diseases. Consistent with an anti-inflammatory function of HGF, IFN-β, the most common im- 4. Role of HGF in inflammatory-mediated disease animal models munomodulatory treatment for MS, was found to directly induce the ex- pression of HGF protein by human monocytes [113]. In MS, data indicate As reviewed here, HGF is a cytokine with pleiotropic effects in im- that cerebrospinal fluid (CSF) levels of HGF correlate negatively with dis- munoregulation and inflammation. In vivo, accumulating evidence ease activity as patients with high inflammatory activity in the CNS have also supports a protective role of HGF in multiple animal models of lower HGF concentrations in the CSF, while treatment with IFN-β or immune-mediated diseases in various organ systems. This includes Copaxone increases the CSF levels of HGF [114]. the classical autoimmune diseases such as rheumatoid arthritis, auto- immune neuroinflammation and autoimmune myocarditis, and proto- 4.3. Graft-versus-host disease (GVHD) typical inflammatory diseases, such as inflammatory bowel disease, asthma and others, suggesting that HGF may suppress a common proin- In a heterotopic cardiac transplantation murine model, HGF was flammatory process. Here, we specifically describe the impact and reported to prolong the survival of allografts through its immuno- mechanism of HGF's anti-inflammatory actions in these different com- modulative potencies [115]. HGF treatment reduced the early expression plex immune-related diseases (see also Table 1). of IFN-γ, a cytokine that plays a central role in acute rejection [116],and 298 N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303 enhanced TGF-β1 expression during the acute phase and IL-10 continu- and Crohn's disease are the two major types. In IBD patients, elevated ously through the acute phase to the chronic phase [115].Thesefindings serum HGF level and mucosal overexpression of HGF and c-Met have support a role for Treg cell-mediated immunosuppression in the protec- been reported [139], suggesting an association with intestinal tissue re- tive effect of HGF in this model [115]. In agreement with these findings, pair. In cell culture, HGF stimulates the growth of gastrointestinal epi- HGF sustains Tregs and prolongs the survival of kidney allografts in thelial cells [140]. Systemic administration of HGF was reported to MHC-inbred CLAWN-miniature swine [117]. HGF was also reported to ameliorate experimental colitis in rats [141,142]. For the treatment of strongly inhibit both acute and chronic GVHD in mouse models of bone IBD in a rat model, HGF was found to ameliorate diarrhea and gross in- marrow transplantation by directly controlling autoimmunity, and in par- flammation [143,144]. HGF gene therapy was reported to markedly ticular by inhibiting the development of autoreactive T cells in the thymus suppress intestinal expression of Th1 cytokines such as IL-12 and IFN- damaged by GVHD [118,119]. HGF was further shown to prevent murine γ, but also IL-1β and TNF, and to decrease the number of CD4+ T cells, lupus, autoimmune sialoadenitis, and cholangitis in a model of chronic neutrophils, and myeloperoxidase activity in intestinal epithelium GVHD by suppressing MHC class II expression by host B cells and immu- [145]. HGF was found to have a synergistic effect with omega-3 in an nogenic DC function, leading to reduced antigen presentation to donor immunologic model of IBD, presumably through a synergistic effect in CD4+ T cells and serum levels of IgG and anti-DNA antibodies [66]. the reduction of inflammation [146]. Collectively, these findings suggest that HGF could have therapeutic applications in the management of in- 4.4. Kidney diseases flammatory bowel disease in humans [145,147].

HGF reduces renal injury in various rodent models of chronic renal 4.7. Lung disease disease, including remnant kidney [120–122], unilateral ureteral obstruc- tion [123,124], and diabetic nephropathy [125]. While the antifibrogenic Pulmonary fibrosis (PF) is an inflammatory interstitial lung disorder actions of HGF are likely to explain most of its beneficial action in these in which apoptosis and fibrinogenesis are central to its formation and de- different models, suppression of renal inflammation may also contribute velopment. In various animal models of PF, administration of HGF or ec- to its protective impact [126–129].Renalinflammation is a central factor topic HGF expression ameliorates fibrosis. In lungs, HGF is produced by contributing to progression of chronic renal disease, in which tubular ep- mesenchymal and bronchial epithelial cells and alveolar macrophages ithelial cells (TEC) are considered to play a prominent role in the influx of [148]. Continuous systemic injection of HGF suppresses murine PF in- inflammatory cells into the interstitium [130]. Collectively, in vivo data duced by bleomycin [149]. HGF was identified as a key ligand to elicit and in vitro studies with human kidney epithelial cells indicate that the myofibroblast apoptosis and extracellular matrix degradation in increas- anti-inflammatory action of HGF is primarily mediated by disrupting ing activities of matrix-metalloproteases (MMP)-2/-9. Because PF is an NF-κB signaling [128,131]. In addition, HGF gene therapy was found to re- inflammatory disorder, its treatment would beneficiate from therapy duce pro-inflammatory cytokines and enhance infiltration of reparative that could further suppress the immune inflammatory response. In- M2 macrophages in glomeruli in a mouse model of injured diabetic kid- creased endogenous HGF levels in mouse lungs following HGF gene ney [78].Thesefindings suggest that HGF therapy generates a microenvi- transfection were shown to reduce the apoptosis in alveolar epithelial ronment prone to the promotion of macrophage-mediated renal tissue cells and decrease both pro-inflammatory cytokine TNF and IL-6 levels repair and regeneration. Endogenous HGF was also reported to attenuate and collagen synthesis after bleomycin injury [150]. Via a mechanism inflammatory response in a rat model of glycerol-induced acute kidney mediated by HGF, instillation of apoptotic cells into bleomycin- injury (AKI) through reduction of leukocyte infiltration and Th1 polariza- stimulated lungs results in reduction in apoptosis and inflammation, tion [132]. Using genetically modified mice that have high blood levels of and in particular in the inhibition of the generation of inflammatory cy- HGF, the HGF/c-Met system was shown to prevent LPS-induced renal, but tokines in macrophages [151]. HGF also potently antagonizes the also liver and vascular, injuries through the inhibition of inflammation profibrotic actions of TGF-β1 [152]. In addition, HGF attenuates allergic and reactive oxygen species production [133]. airway inflammation and airway hyper-responsiveness in a murine model [153]. Altogether, these studies suggest that HGF is an attractive 4.5. Cardiac diseases target for the treatment of PF [154]. Finally, HGF was reported to sup- press allergic airway inflammation in vitro and in vivo by blocking the In the heart, HGF exerts potent anti-apoptotic/cardioprotective APC function of DCs and subsequent Th1 and Th2 immune responses in- actions in rats subjected to myocardial infarction [134,135] and contrib- duced by antigen sensitization [65]. utes to cardiac regeneration after myocardial infarction [136].HGFfur- ther improves the cardiac function in an experimental model of 4.8. Liver disease dilated cardiomyopathy [137]. The HGF receptor c-Met is only weakly expressed in adult cardiomyocytes, but both myocardial HGF and c- HGF was reported to prevent liver failure in multiple animal models Met are substantially increased following heart injury [134,135].Inan including endotoxin-induced acute liver failure [155,156]. Consistent established experimental model of autoimmune myocarditis, HGF was with the key role played by cytokines in various models of acute liver fail- found to markedly improve cardiac function by inducing Th2 cytokines ure, evidence supports that the protective effect of HGF might be partial- and suppressing T cell proliferation and production of IFN-γ, and reduc- ly mediated through enhanced production by hepatocytes of IL-1 ing apoptosis of cardiomyocytes [51]. Finally, in an animal model of ge- receptor antagonist (IL-1Ra), a natural inhibitor of inflammation [157]. netically determined cardiomyopathy and heart failure, HGF gene Also HGF has been demonstrated to limit IFN-γ-induced cytotoxicity in therapy was found to display antifibrotic actions dependent on the inhi- mouse hepatocytes [158] and to inhibit excessive activation of Fas- bition of collagen synthesis through inhibition of TGF-β expression, and mediated signal pathway, which contributes most to the development degradation of collagen through activation of matrix metalloproteinase- of fulminant hepatic failure caused by hepatitis virus infection or endo- 1 and urokinase-type plasminogen activator (uPA) [138]. Collectively, toxin [159]. HGF was also shown in viral model of hepatitis to modulate these studies suggest that HGF may be useful to protect against myocar- DC activation and CD8+ T cell priming, thereby limiting the immune- dial injury and inflammation in cardiomyopathy. mediated inflammation and damage in the liver [160].

4.6. Inflammatory bowel disease (IBD) 5. HGF as therapeutic agent

Inflammatory bowel disease (IBD) is a group of inflammatory condi- Because exogenously administered HGF proteins vanish very rapidly tions of the colon and small intestine, among which ulcerative colitis from organs [161], different strategies have been developed to achieve N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303 299 effective HGF delivery in the target organs or to generate high serum accumulation of eosinophils and Th2 lymphocytes in the airways [153]. levels of this factor in these different disease animal models. Biodegrad- HGF also prevents lupus nephritis in a murine lupus model of chronic able gelatin hydrogels as a carrier were shown to effectively achieve a GVHD by decreasing antigen presentation by both DCs and B cells, there- sustained and controlled delivery of HGF resulting in angiogenic effect by inhibiting Th2 generation [66]. In a murine model of cardiac transplan- around the implanted site [162] and in inducing successful liver regen- tation, HGF reduces acute and chronic rejection of the allograft by eration in a rat model of liver cirrhosis [163]. This therapeutic method promoting allograft tolerance presumably through an immunosuppres- was also successful in reducing incidence and severity of mouse models sive mechanism mediated by Tregs [115]. In autoimmune neuroinflam- of autoimmune arthritis and neuroinflammation [67,83]. This strategy mation, HGF attenuates disease severity by suppressing Th1/Th17 however is limited, as in addition to its instability, HGF is difficult to pu- inflammation [112] and promoting Treg generation through action on rify in its heterodimeric biologically active form. Different delivery sys- tolerogenic DCs [68,83]. In autoimmune arthritis, HGF diminishes the se- tems for HGF have been also evaluated, including the intravenous verity and incidence of experimental RA with concomitant up-regulation delivery of HGF gene in mice via a hydrodynamics-based transfection of Th2 and IL-10-producing CD4+ T cells and suppression of Th17 cells system [164]. This strategy achieved sustained, long-term, high levels through modulation of DC function [67]. Tolerogenic DC activation by of exogenous HGF expression in mice [165] and potently suppressed HGF requires critical signaling pathways that ultimately result in disrup- the development of allergic airway inflammation [65]. One must how- tion of the inflammatory actions of NF-κB [69,70,83]. HGF/c-Met signaling ever point out that such observations are preliminary, and do not estab- was reported to act as an endogenous regulator of islet inflammation and lish the safety of HGF administration over the long-term, which may autoimmunity likely through downregulation of NF-κB signaling pathway include potential adverse events such as cancer. New studies also sug- [175]. Likewise, HGF/c-Met system was defined as an endogenous regula- gest a potential use of gene-modified mesenchymal stem cells (MSCs) tor of islet inflammation and autoimmunity in type I diabetes likely as gene therapy delivery vehicles [166]. In a mouse model of lung injury, through downregulation of NF-κB signaling [175]. The direct anti- the delivery of MSCs genetically engineered to express HGF reduced the inflammatory action of HGF in chronic renal disease is also likely attribut- secretion and expression of pro-inflammatory cytokines, including TNF, able to the blockade of pro-inflammatory NF-κB signaling in tubular epi- IFN-γ, IL-6, and intercellular adhesion molecule-1 (ICAM-1), and in- thelial cells [129,176,177]. HGF attenuates acute colitis by facilitating crease the expression of anti-inflammatory cytokine IL-10 [167]. This intestinal wound repair and via local anti-inflammatory action [178],in- novel approach would overcome the hurdle of the limited duration of cluding the suppression of Th1-related cytokines, as well as the number the therapy attained with gene delivery vectors or protein delivery of CD4+ T cells, neutrophils, and myeloperoxidase activity in intestinal and the tall costs associated with protein therapy because of the need epithelium [145]. Enhanced HGF degranulation by polymorphonuclear for important doses. Of particular interest, HGF was reported to mediate leukocytes in patients with systemic inflammatory response syndrome human MSC-stimulated functional recovery in animal models of MS (SIRS) may also play an important role in tissue repair or organ regener- [112]. In addition to MSCs, injection of platelet-rich plasma (PRP), a ation in the injured tissue in the systemic inflammatory response [103]. promising new biological therapeutic agent for chronic injuries, was Finally, HGF exerts protective actions in acute ischemic and inflammatory shown to exert anti-inflammatory effects on injured tendons through injuries by preventing apoptosis and promoting angiogenesis [134,179], HGF by suppressing IL-1β-induced gene expression of cytochrome c ox- as well as by attenuating ischemia-induced-apoptotic death [180] and is- idase subunit I (COX-1), COX-2, and membrane-associated prostaglan- chemia- or toxic-induced insults [181–183]. HGF may also represent a din E synthase-1 (mPGES-1) [168]. Likewise, HGF was found to mediate novel strategy for the treatment of other inflammatory disorders, such the molecular basis of anti-inflammatory action of PRP on human as in skin wound repair, [184] or in inflammation-induced acute liver fail- chondrocytes by reducing the transactivating activity of NF-κB and de- ure, where HGF exerts anti-inflammatory effects by modulation of cyto- creasing the expression of COX-2 and C-X-C chemokine receptor type 4 kine synthesis [157]. (CXCR4) target genes [111]. Altogether, these new medical technolo- Over the last few years, rapid progress in our understanding of mo- gies that eliminate the need for gene delivery vectors or protein delivery lecular and cellular aspects of immune function offers a vision of more may rely for the most part for their content of HGF. effective therapies for autoimmune and inflammatory disorders. Recent Based on the various protective roles of HGF in in vitro and in vivo an- examples in the autoimmune field are the identification of critical regu- imal models, human clinical trials of HGF therapy were designed over the lators of T cell tolerance induction, such as the autoimmune regulator recent years in diseases where inflammation is suspected to contribute to (AIRE), or maintenance, such as the cytotoxic T-lymphocyte antigen 4 thetissuedamage[169]. A phase I/II clinical trial of recombinant human (CTLA-4) and PD-L1 [185–187]. Although still largely underappreciated, HGF (rhHGF) has been initiated for the treatment of acute spinal cord in- new and compelling data as summarized in this review indicate HGF as jury (SCI). Attenuation of the inflammatory response to SCI may limit the a central regulator of inflammation and autoimmunity. It has been extent of tissue injury and, accordingly, HGF therapy may help to reduce established that HGF exerts multiple immunomodulatory functions or the consequent disability [170]. Finally, both the dosing and primary safe- disease-suppressive activities across several disease models and organ ty evaluation was successfully finished in a phase 1a clinical trial of rhHGF systems. Many of the therapeutic effects of HGF can be attributed to for US patients with renal disease, where inflammation is believed to play its ability to induce immune tolerance through common immune a major role in the pathophysiology of this condition. checkpoint inhibitors. In this regard, we recently showed that HGF treatment increases the levels of PD-L1 expression by DCs [83] and the 6. Concluding remarks inhibitory counter-receptor CTLA-4 molecules expressed on T cells [92]. By inducing GILZ in DCs, we further established that HGF repro- In this part, we summarize current knowledge of how the HGF/c-Met duces the mechanism of immune regulation induced by potent immu- pathway contributes to the regulation of immune-mediated disorders. nomodulatory factors such as IL-10, TGF-β1, and glucocorticoids [83]. HGF frequently counteracts TGF-β1, a potent fibrogenic and immunosup- HGF may thus represent a useful new target for the treatment of pressive cytokine [171–174], suggesting that HGF might be an immuno- human autoimmune and inflammatory diseases. potentiator. Accumulating data however indicate that HGF exerts protective autoimmune activities. HGF ameliorates the progression of ex- 7. Future directions perimental autoimmune myocarditis, a Th1-mediated model, by decreas- ing IFN-γ production and increasing Th2 responses [51]. HGF treatment An interesting avenue for future research would consist of develop- potently attenuates experimental allergic airway inflammation by sup- ing methods to control endogenous HGF levels for disease therapy. It is pressing both the APC function of DCs, thus down-regulating antigen- tempting to hypothesize that the shedding of c-Met could represent a induced Th1- and Th2-type immune responses [65], and the novel mechanism for regulating the anti-inflammatory effects of HGF. 300 N. Molnarfi et al. / Autoimmunity Reviews 14 (2015) 293–303

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