Early infiltrating macrophage subtype correlates with late-stage phenotypic outcome in a mouse model of hepatorenal fibrocystic disease

• Published in: Laboratory investigation Vol. 101; no. 10; pp. 1382 - 1393
• Main Authors: Zimmerman, Kurt A., Song, Cheng J., Aloria, Ernald J.G., Li, Zhang, Zhou, Juling, Bland, Sarah J., Yashchenko, Alex, Crossman, David K., Mrug, Michal, Yoder, Bradley K.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.10.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/31; 38/91; 631/250/2504/342; 692/699/1585/1589; Animal models; Animals; Bile ducts; CC chemokine receptors; CCR2 protein; Cilia; Correlation; Cytokines - metabolism; Disease Models, Animal; Epithelium; Female; Fibrosis; Gene sequencing; Hypotheses; Inbreeding; Laboratory Medicine; Liver; Liver - metabolism; Liver Cirrhosis; Macrophages; Macrophages - classification; Macrophages - immunology; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Mutation; Pathology; Phenotype; Phenotypes; Tissue analysis
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00627-0

Hepatorenal fibrocystic disease (HRFCD) is a genetically inherited disorder related to primary cilia dysfunction in which patients display varying levels of fibrosis, bile duct expansion, and inflammation. In mouse models of HRFCD, the phenotype is greatly impacted by the genetic background in which the mutation is placed. Macrophages are a common factor associated with progression of HRFCD and are also strongly influenced by the genetic background. These data led us to hypothesize that macrophage subtypes that change in relation to the genetic background are responsible for the variable phenotypic outcomes in HRFCD. To test this hypothesis, we utilized a mouse model of HRFCD (Ift88Orpk mice) on the C57BL/6 and BALB/c inbred backgrounds that have well-documented differences in macrophage subtypes. Our analyses of infiltrating macrophage subtypes confirm that genetic strain influences the subtype of infiltrating macrophage present during normal postnatal liver development and in Ift88Orpk livers (Ly6clo in C57BL/6 vs Ly6chi in BALB/c). Each infiltrating macrophage subtype was similarly associated with a unique phenotypic outcome as analysis of liver tissue shows that C57BL/6 Ift88Orpk mice have increased bile duct expansion, but reduced levels of fibrosis compared to BALB/c Ift88Orpk livers. RNA sequencing data suggest that the ability to infiltrate macrophage subtypes to influence the phenotypic outcome may be due to unique ligand-receptor signaling between infiltrating macrophages and cilia dysfunctional biliary epithelium. To evaluate whether specific macrophage subtypes cause the observed phenotypic divergence, we analyzed the liver phenotype in BALB/c Ift88Orpk mice on a CCR2−/− background. Unexpectedly, the loss of Ly6chi macrophages, which were strongly enriched in BALB/c Ift88Orpk mice, did not significantly alter liver fibrosis. These data indicate that macrophage subtypes may correlate with HRFCD phenotypic outcome, but do not directly cause the pathology. In this study, the authors tested the hypothesis that differences in infiltrating macrophage subtypes between C57BL/6 and BALB/c mouse models of hepatorenal fibrocystic disease were responsible for the divergent phenotypic outcome s observed in the liver. Despite the significant correlation between infiltrating macrophage subtype and phenotypic outcome, these correlations were not causative of the liver pathology.