Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway.
Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included. 20 out of 32 patients were treated with docosahexaenoic acid for 18 months and biopsies at the baseline and after 18 months were included. Hepatic progenitor cell activation, macrophage subsets and Wnt/β-catenin pathway were evaluated by immunohistochemistry and immunofluorescence. Our results indicated that in pediatric non-alcoholic fatty liver disease, pro-inflammatory macrophages were the predominant subset. Macrophage polarization was correlated with Non-alcoholic fatty liver disease Activity Score, ductular reaction, and portal fibrosis; docosahexaenoic acid treatment determined a macrophage polarization towards an anti-inflammatory phenotype in correlation with the reduction of serum inflammatory cytokines, with increased macrophage apoptosis, and with the up-regulation of macrophage Wnt3a expression; macrophage Wnt3a expression was correlated with β-catenin phosphorylation in hepatic progenitor cells and signs of commitment towards hepatocyte fate. In conclusion, macrophage polarization seems to have a key role in the progression of pediatric non-alcoholic fatty liver disease; the modulation of macrophage polarization could drive hepatic progenitor cell response by Wnt3a production.
Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
Guido
G
Carpino
Unit of Liver Research, Bambino Gesù Children's Hospital, Rome, Italy.
Valerio
V
Nobili
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
Anastasia
A
Renzi
Unit of Liver Research, Bambino Gesù Children's Hospital, Rome, Italy.
Cristiano
C
De Stefanis
Department of Radiobiology and Human Health, ENEA, Rome, Italy.
Laura
L
Stronati
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
Antonio
A
Franchitto
Unit of Liver Research, Bambino Gesù Children's Hospital, Rome, Italy.
Anna
A
Alisi
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
Paolo
P
Onori
Unit of Pathology, Bambino Gesù Children's Hospital, Rome, Italy.
Rita
R
De Vito
Research, Central Texas Veterans Health Care System, Department of Medicine, Scott & White Digestive Disease Research Center, Scott & White and Texas A&M Health Science Center College of Medicine, Temple, Texas, United States of America.
Gianfranco
G
Alpini
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy.
Eugenio
E
Gaudio
D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001706:Biopsy; D002648:Child; D018450:Disease Progression; D004281:Docosahexaenoic Acids / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C495270:CTNNB1 protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin; D004281:Docosahexaenoic Acids