title: Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH).
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 8weeks. In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated 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 vacuolated 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.
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Aastha
authors.initials: A
authors.lastname: Jindal
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bruzzì
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sutti
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Locatelli
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bozzola
authors.affiliation: Dept of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Paternostro
authors.affiliation: Dept of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.affiliation: Dept. of Health Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy; Interdisciplinary Research Centre for Autoimmune Diseases, University "Amedeo Avogadro" of East Piedmont, Novara, Italy. Electronic address: emanuele.albano@med.unipmn.it.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Albano
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004032:Diet; D018450:Disease Progression; D005355:Fibrosis; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008264:Macrophages / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D017305:Annexin A1; D000950:Antigens, Ly; D039481:CD11b Antigen; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C082939:Llgl1 protein, mouse; C494192:Ly-6C antigen, mouse; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000410:Alanine Transaminase; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: Annexin A1; Liver inflammation; Macrophages; Nonalcoholic fatty liver disease