title: Lack of CC chemokine ligand 2 differentially affects inflammation and fibrosis according to the genetic background in a murine model of steatohepatitis.
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.
authors.affiliation: Dipartimento di Medicina Interna, University of Florence, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Galastri
authors.forename: Elena
authors.initials: E
authors.lastname: Zamara
authors.forename: Stefano
authors.initials: S
authors.lastname: Milani
authors.forename: Erica
authors.initials: E
authors.lastname: Novo
authors.forename: Angela
authors.initials: A
authors.lastname: Provenzano
authors.forename: Wanda
authors.initials: W
authors.lastname: Delogu
authors.forename: Francesco
authors.initials: F
authors.lastname: Vizzutti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sutti
authors.forename: Irene
authors.initials: I
authors.lastname: Locatelli
authors.forename: Nadia
authors.initials: N
authors.lastname: Navari
authors.forename: Elisa
authors.initials: E
authors.lastname: Vivoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caligiuri
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000276:immunology; D013045:Species Specificity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D004041:Dietary Fats; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta