title: CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis.
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.
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sutti
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Locatelli
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruzzì
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Aastha
authors.initials: A
authors.lastname: Jindal
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vacchiano
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bozzola
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Via Solaroli 17, 28100 Novara, Italy emanuele.albano@med.unipmn.it.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000950:Antigens, Ly / Q000235:genetics; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002796:Choline Deficiency; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D018450:Disease Progression; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008715:Methionine / Q000172:deficiency; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C494192:Ly-6C antigen, mouse; D019707:Receptors, Chemokine; D013440:Sulfides; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D008715:Methionine; C025451:sodium bisulfide
keywords: CX3CR1; chronic inflammation; dendritic cells; liver fibrosis; macrophages; non-alcoholic fatty liver disease