Emanuele Albano

Amedeo Avogadro University of Eastern Piedmont, Novara, Piedmont, Italy

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Publications (242)1431.51 Total impact

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    ABSTRACT: Liver monocytes play a major role in the development of NASH (non-alcoholic steatohepatitis). In inflamed tissues, monocytes can differentiate in both macrophages and dendritic cells. In the present study, we investigated the role of moDCs (monocyte-derived inflammatory dendritic cells) in experimental steatohepatitis induced in C57BL/6 mice by feeding on a MCD (methionine/choline-deficient) diet. The evolution of steatohepatitis was characterized by an increase in hepatic CD45(+)/CD11b(+) myeloid cells displaying the monocyte/macrophage marker F4-80(+). In the early phases (4 weeks of treatment), Ly6C(high)/CD11b(+)/F4-80(+) inflammatory macrophages predominated. However, their frequency did not grow further with the disease progression (8 weeks of treatment), when a 4-fold expansion of CD11b(+)/F4-80(+) cells featuring the fractalkine receptor (CX3CR1) was evident. These CX3CR1(+) cells were also characterized by the combined expression of inflammatory monocyte (Ly6C, CD11b) and dendritic cell (CD11c, MHCII) markers as well as by a sustained TNFα (tumour necrosis factor α) production, suggesting monocyte differentiation into inflammatory moDCs. The expansion of TNFα-producing CX3CR1(+) moDCs was associated with an elevation in hepatic and circulating TNFα level and with the worsening of parenchymal injury. Hydrogen sulfide (H2S) has been shown to interfere with CX3CR1 up-regulation in monocyte-derived cells exposed to pro-inflammatory stimuli. Treating 4-week-MCD-fed mice with the H2S donor NaHS while continuing on the same diet prevented the accumulation of TNFα-producing CX3CR1(+) moDCs without interfering with hepatic macrophage functions. Furthermore, NaHS reduced hepatic and circulating TNFα levels and ameliorated transaminase release and parenchymal injury. Altogether, these results show that inflammatory CX3CR1(+) moDCs contributed in sustaining inflammation and liver injury during steatohepatitis progression.
    Clinical Science 11/2015; 129(9):797-808. DOI:10.1042/CS20150053 · 5.60 Impact Factor
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    ABSTRACT: The growing diffusion of nonalcoholic fatty liver disease (NAFLD) is a consequence of the worldwide increase in the prevalence of obesity. Oxidative stress is widely recognized to play a pivotal role in NAFLD evolution to nonalcoholic steatohepatitis (NASH). Here we review recent evidence suggesting that oxidative stress-derived antigens originating within fatty livers stimulate both humoral and cellular adaptive immune responses and the possible mechanisms involved in sustaining hepatic inflammation in NASH.
    World Journal of Hepatology 07/2015; 7(13):1725-9. DOI:10.4254/wjh.v7.i13.1725
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    ABSTRACT: Nonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine-choline deficient (MCD) diet up to 8 weeks. In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolized cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat-laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-α) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolized macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80(+) cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size. We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses. Copyright © 2015. Published by Elsevier Inc.
    Experimental and Molecular Pathology 06/2015; 62(1). DOI:10.1016/j.yexmp.2015.06.015 · 2.71 Impact Factor
  • S. Sutti · F. Heymann · J. Peusquens · C. Trautwein · E. Albano · F. Tacke ·

    Journal of Hepatology 04/2015; 62:S202-S203. DOI:10.1016/S0168-8278(15)30033-7 · 11.34 Impact Factor

  • Journal of Hepatology 04/2015; 62:S700. DOI:10.1016/S0168-8278(15)31147-8 · 11.34 Impact Factor
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    ABSTRACT: To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (WT) and glutathione S-transferase A4-4 null (GSTA4-/-) mice for 40 d. GSTA4-/- mice were crossed with peroxisome proliferator-activated receptor-α null mice (PPARα-/-) and effects of EtOH in the resulting dKO mice were compared to the other strains. EtOH increased lipid peroxidation in all except WT mice (P< 0.05). Increased steatosis, mRNA expression of inflammatory markers: CXCL2 and tumor necrosis factor α (TNF) and of smooth muscle actin (αSMA) were observed in EtOH GSTA4-/- compared to EtOH WT mice (P<0.05). EtOH PPARα-/- mice had increased steatosis, serum alanine aminotransferase (ALT) and hepatic CD3+ T-cell populations, and elevated mRNA encoding CD14, CXCL2, TNFα, IL-6, CD138, transforming growth factor β(TGFβ), platelet derived growth factor receptor β (PDGFR), matrix metalloproteinase (MMP) 9 and 13, αSMA and collagen type 1 compared to EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-HNE adducts and serum antibodies against malondialdehyde-adducts compared to EtOH-feeding of GSTA4-/-, PPARα-/- and WT mice (P<0.05). ALT was higher in EtOH dKO mice compared to all other groups (P<0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF and CD14, histological evidence of fibrosis, and increased PDGFR, MMP 9 and 13 mRNAs, compared to the EtOH GSTA4-/- or EtOH PPARα-/- genotype (P<0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling and fibrosis. Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    AJP Gastrointestinal and Liver Physiology 12/2014; 308(5):ajpgi.00154.2014. DOI:10.1152/ajpgi.00154.2014 · 3.80 Impact Factor
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    Salvatore Sutti · Cristina Rigamonti · Matteo Vidali · Emanuele Albano ·
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    ABSTRACT: Autoimmune reactions involving cytochrome P4502E1 (CYP2E1) are a feature of idiosyncratic liver injury induced by halogenated hydrocarbons and isoniazid, but are also detectable in about one third of the patients with advanced alcoholic liver disease (ALD) and chronic hepatitis C (CHC). In these latter the presence of anti-CYP2E1 auto-antibodies is an independent predictor of extensive necro-inflammation and fibrosis and worsens the recurrence of hepatitis following liver transplantation, indicating that CYP2E1-directed autoimmunity can contribute to hepatic injury. The molecular characterization of the antigens recognized by anti-CYP2E1 auto-antibodies in ALD and CHC has shown that the targeted conformational epitopes are located in close proximity on the molecular surface. Furthermore, these epitopes can be recognized on CYP2E1 expressed on hepatocyte plasma membranes where they can trigger antibody-mediated cytotoxicity. This does not exclude that T cell-mediated responses against CYP2E1 might also be involved in causing hepatocyte damage. CYP2E1 structural modifications by reactive metabolites and molecular mimicry represent important factors in the breaking of self-tolerance against CYP2E1 in, respectively, ALD and CHC. However, genetic or acquired interferences with the mechanisms controlling the homeostasis of the immune system are also likely to contribute. More studies are needed to better characterize the impact of anti-CYP2E1 autoimmunity in liver diseases particularly in relation to the fact that common metabolic alterations such as obesity and diabetes stimulates hepatic CYP2E1 expression. Copyright © 2014. Published by Elsevier B.V.
    11/2014; 3C:72-78. DOI:10.1016/j.redox.2014.11.004
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    ABSTRACT: Unlabelled: Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. However, its role in chronic settings is less investigated. Because changes in AnxA1 expression within adipose tissue characterize obesity in mice and humans, we queried a possible role for AnxA1 in the pathogenesis of nonalcoholic steatohepatitis (NASH), a disease commonly associated with obesity. NASH was induced in wild-type (WT) and AnxA1 knockout (AnxA1 KO) C57BL/6 mice by feeding a methionine-choline deficient (MCD) diet up to 8 weeks. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury. This mediator was also detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. In both humans and rodents, AnxA1 production was selectively localized in liver macrophages. NASH in AnxA1 KO mice was characterized by enhanced lobular inflammation resulting from increased macrophage recruitment and exacerbation of the M1 phenotype. Consistently, in vitro addition of recombinant AnxA1 to macrophages isolated from NASH livers down-modulated M1 polarization through stimulation of interleukin-10 production. Furthermore, the degree of hepatic fibrosis was enhanced in MCD-fed AnxA1 KO mice, an effect associated with augmented liver production of the profibrotic lectin, galectin-3. Accordingly, AnxA1 addition to isolated hepatic macrophages reduced galectin-3 expression. Conclusions: Macrophage-derived AnxA1 plays a functional role in modulating hepatic inflammation and fibrogenesis during NASH progression, suggesting the possible use of AnxA1 analogs for therapeutic control of this disease.
    Hepatology 08/2014; 60(2). DOI:10.1002/hep.27141 · 11.06 Impact Factor
  • Mario Strazzabosco · Luca Fabris · Emanuele Albano ·
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    ABSTRACT: In recent years, an increasing number of reports have shown the involvement of osteopontin (OPN), a pleiotropic cytokine and an important component of the extracellular matrix (ECM), in the pathogenesis of liver injury and the development of fibrosis.1 ,2 OPN is also frequently overexpressed in hepatocellular carcinoma (HCC), where it modulates HCC growth, invasion and metastasis,2 and in cholangiocarcinoma, where its expression bears prognostic significance. Previous studies3 have shown that in injured livers OPN is expressed by hepatic stellate cells (HSC) and upregulates collagen I production. Interestingly, in HSC, OPN expression appears to be downstream of SOX9, a Hedgehog- and Notch-controlled transcription factor that is expressed also in biliary cells and hepatic progenitor cells (HPC)/hepatocytes committed to the biliary fate.4-6 In this issue of Gut, two papers investigate the role of OPN in HPC-driven ductular reaction (DR) in relation to the progression of liver fibrosis.7 ,8 DR, a histological lesion present in most chronic liver diseases, is a dynamic, multicellular complex characterised by the presence of ‘reactive’ ductular epithelial cells, arranged in irregular strings along the margins of the portal tract in close contact with mesenchymal, inflammatory and endothelial cells. Reactive ductular cells acquire novel functions including the secretion of cytokines, chemokines, growth factors and angiogenic factors, enabling them to establish intense paracrine communications with … [Full text of this article]
    Gut 07/2014; 63(11). DOI:10.1136/gutjnl-2014-307712 · 14.66 Impact Factor

  • Journal of Hepatology 04/2014; 60(1):S151. DOI:10.1016/S0168-8278(14)60421-9 · 11.34 Impact Factor
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    ABSTRACT: Unlabelled: Previous studies have shown that human nonalcoholic steatohepatitis (NASH) is often associated with the presence of circulating antibodies against protein adducted by lipid peroxidation products. Here we used the methionine-choline deficient (MCD) model of NASH to characterize the possible involvement of adaptive immunity in NASH. In mice fed up to 8 weeks with the MCD diet the extension of liver injury and lobular inflammation paralleled the development of immunoglobulin G (IgG) against malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-derived antigens as well as with the hepatic recruitment of CD4(+) and CD8(+) T-lymphocytes responsive to the same antigens. Moreover, in these animals the individual IgG reactivity against MDA-adducts positively correlated with transaminase release and hepatic tumor necrosis factor alpha (TNF-α) expression. To substantiate the role of immune responses triggered by oxidative stress in the progression of NASH, mice were immunized with MDA-adducted bovine serum albumin (MDA-BSA) before feeding the MCD diet. MDA-BSA immunization did not affect control mice livers, but further stimulated transaminase release, lobular inflammation, and the hepatic expression of proinflammatory cytokine in MCD-fed mice. The increased severity of NASH in immunized MCD-fed mice involved liver recruitment and the T helper (Th)-1 activation of CD4(+) T cells that, in turn, further stimulated macrophage M1 responses. Moreover, hepatic fibrosis was also evident in these animals in relation with an IL-15-mediated increase of natural killer T-cells (NKT) and the up-regulation in liver production of osteopontin by NKT cells and hepatic macrophages. Conclusion: These results indicate that oxidative stress can contribute to the progression of NASH by stimulating both humoral and cellular immune responses, pointing to the possible role of adaptive immunity in the pathogenesis of the disease.
    Hepatology 03/2014; 59(3). DOI:10.1002/hep.26749 · 11.06 Impact Factor

  • Thrombosis and Haemostasis 10/2013; 111(2). DOI:10.1160/TH13-06-0525 · 4.98 Impact Factor
  • S. Sutti · I. Locatelli · A. Jindal · M. Vacchiano · C. Bozzola · E. Albano ·

    Journal of Hepatology 04/2013; 58:S525. DOI:10.1016/S0168-8278(13)61301-X · 11.34 Impact Factor

  • Journal of Hepatology 04/2013; 58:S512. DOI:10.1016/S0168-8278(13)61267-2 · 11.34 Impact Factor

  • Journal of Hepatology 04/2013; 58:S511. DOI:10.1016/S0168-8278(13)61264-7 · 11.34 Impact Factor
  • I. Locatelli · S. Sutti · A. Jindal · M. Vacchiano · C. Bozzola · E. Albano ·

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    ABSTRACT: Growing evidence indicates that NF-kB activation contributes to the pathogenesis of non-alcoholic steatohepatisis (NASH). Among the NF-kB sub-units, p50/NFkB1 has regulatory activities down-modulating NF-kB-mediated responses. In this study we investigated the effects of NFKB1 deficiency on the progression of NASH induced by feeding mice with a methionine-choline deficient (MCD) diet. Following 4 weeks on the MCD diet, steatosis, ALT release, hepatocyte apoptosis, lobular inflammation and TNF-α production were higher in NFKB1-ko than in wild-type (WT) mice. NFkB1-/- mice also showed appreciable centrilobular collagen deposition, increased number of activated hepatic stellate cells and higher type-I procollagen-α and TIMP-1 mRNA expression. Despite NF-kBp50 homodimers regulate macrophage activation, the number of hepatic macrophages and liver mRNAs for inducible NO synthase, IL-12p40, CCL2, CXCL10 were comparable in the two strains. NASH was associated with an increase in liver infiltrating T-lymphocytes that was more evident in MCD-fed NFKB1-/- than in similarly treated WT mice. Flow-cytorimetry showed that T cell recruitment involved effector CD8+-T cells without changes in the helper CD4+ T-cell fraction. Furthermore, while NASH lowered hepatic natural killer T cells (NKT) in WT mice, the NKT pool was selectively increased in the livers of MCD-fed NFkB1-/- mice. Such a NKT recruitment was associated with an early over-expression of IL-15, a cytokine controlling NKT cell survival and maturation. In the livers of MCD-fed NFkB1-/- mice, but not in those of WT littermates, we also observed an up-regulation in the production of NKT-related cytokines IFN-γ and osteopontin. Altogether these results indicated that NF-KB1 down-modulation enhanced NASH progression to fibrosis by favoring NKT cell recruitment, stressing the contribution of NKT cells in the pathogenesis of NASH.
    Clinical Science 09/2012; 124(4). DOI:10.1042/CS20120289 · 5.60 Impact Factor
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    ABSTRACT: Expression of CCL2 (CC chemokine ligand 2) (or monocyte chemoattractant protein-1) regulates inflammatory cell infiltration in the liver and adipose tissue, favouring steatosis. However, its role in the pathogenesis of steatohepatitis is still uncertain. In the present study, we investigated the development of non-alcoholic steatohepatitis induced by an MCD diet (methionine/choline-deficient diet) in mice lacking the CCL2 gene on two different genetic backgrounds, namely Balb/C and C57/Bl6J. WT (wild-type) and CCL2-KO (knockout) mice were fed on a lipid-enriched MCD diet or a control diet for 8 weeks. In Balb/C mice fed on the MCD diet, a lack of CCL2 was associated with lower ALT (alanine transaminase) levels and reduced infiltration of inflammatory cells, together with a lower generation of oxidative-stress-related products. Sirius Red staining demonstrated pericellular fibrosis in zone 3, and image analysis showed a significantly lower matrix accumulation in CCL2-KO mice. This was associated with reduced hepatic expression of TGF-β (transforming growth factor-β), type I procollagen, TIMP-1 (tissue inhibitor of metalloproteinases-1) and α-smooth muscle actin. In contrast, in mice on a C57Bl/6 background, neither ALT levels nor inflammation or fibrosis were significantly different comparing WT and CCL2-KO animals fed on an MCD diet. In agreement, genes related to fibrogenesis were expressed to comparable levels in the two groups of animals. Comparison of the expression of several genes involved in inflammation and repair demonstrated that IL (interleukin)-4 and the M2 marker MGL-1 (macrophage galactose-type C-type lectin 1) were differentially expressed in Balb/C and C57Bl/6 mice. No significant differences in the degree of steatosis were observed in all groups of mice fed on the MCD diet. We conclude that, in experimental murine steatohepatitis, the effects of CCL2 deficiency are markedly dependent on the genetic background.
    Clinical Science 04/2012; 123(7):459-71. DOI:10.1042/CS20110515 · 5.60 Impact Factor
  • I. Locatelli · S. Sutti · M. Vacchiano · C. Bozzola · E. Albano ·

    Journal of Hepatology 04/2012; 56:S493-S494. DOI:10.1016/S0168-8278(12)61259-8 · 11.34 Impact Factor

  • Journal of Hepatology 04/2012; 44:S9. DOI:10.1016/S1590-8658(12)60026-7 · 11.34 Impact Factor

Publication Stats

8k Citations
1,431.51 Total Impact Points


  • 1999-2015
    • Amedeo Avogadro University of Eastern Piedmont
      • Interdisciplinary Research Center of Autoimmune Diseases IRCAD
      Novara, Piedmont, Italy
  • 2009
    • Royal Prince Alfred Hospital
      Camperdown, New South Wales, Australia
  • 2006
    • Università del Piemonte Orientale
      Alessandria, Piedmont, Italy
  • 2004
    • Università degli Studi di Genova
      Genova, Liguria, Italy
  • 2001-2004
    • Newcastle University
      Newcastle-on-Tyne, England, United Kingdom
  • 1982-1998
    • Università degli Studi di Torino
      • Department of Medical Science
      Torino, Piedmont, Italy
  • 1997
    • Karolinska Institutet
      • Institute of Environmental Medicine - IMM
      Solna, Stockholm, Sweden
  • 1995
    • Ospedale Ordine Mauriziano di Torino, Umberto I
      Torino, Piedmont, Italy
  • 1994
    • Louisiana State University
      • Biodynamics Institute
      Baton Rouge, Louisiana, United States
  • 1980-1993
    • Brunel University London
      अक्सब्रिज, England, United Kingdom
  • 1989
    • University of Pavia
      Ticinum, Lombardy, Italy