Growing evidence implicates portal inflammation as a key predictor of histological progression of NAFLD. We find more hypothesise that the manifestation of portal fibrosis and a pro-fibrogenic DR is driven by cross-talk between diverse infiltrating immune cells. Although numerous cytokines and multiple individual cell types have been implicated in NAFLD pathogenesis, the composition of the portal and peri-ductal inflammatory infiltrate has not been systematically investigated. Methods: Liver biopsy sections from 32 NAFLD
patients were immunostained for keratin-7 to highlight the DR, and co-stained for markers of candidate cellular components of the portal inflammatory infiltrate, including CD3, CD8, CD20, CD68, neutrophil elastase (NE), IL-17 and MMP-9. Fresh-frozen liver biopsy samples were available from 23 NAFLD patients for analysis of Collagen-1A and inflammatory gene expression (TGFβ, IL-1β, TNFα, IL-6, IFN-γ, IL-4 and IL-10). Results: Inflammatory cells within the portal tracts were more numerous than centrilobular regions. The portal inflammatory compartment was comprised of a mix of inflammatory cells, including T cells, B cells, macrophages and neutrophils. Significant portal infiltration was not observed until the presence of progressive NASH (fibrosis
stage 2–4) (all P < 0.05) with the exception of macrophage GSK-3 inhibitor review numbers, which increased with the appearance of simple steatosis (P < 0.01) as well as progressive NASH (P < 0.001) when compared with non-diseased control livers. Portal inflammatory cells were present in the peri-ductular inflammatory niche and cell numbers correlated with increasing grade
of DR (all P < 0.05) and stage of fibrosis (all P < 0.001). Collagen-1A mRNA was elevated in patients with simple steatosis and highest in progressive tuclazepam NASH (P < 0.001). TNFα, IL-1β and IL-6 were highly expressed with progressive NASH (P < 0.05) whereas TGFβ, IFN-γ, IL-4 and IL-10 showed no association with disease state and progression. Elevated levels of pro-inflammatory cytokines TNFα and IL-1β occurred before significant portal inflammatory infiltration (P < 0.05). Functional markers highlighted IL-17 production by a subset of neutrophils and MMP-9 by a subset of portal and lobular macrophages. Conclusion: Cell phenotypes and subsequent signalling are greatly influenced by their microenvironments. A modified hepatic inflammatory environment likely influences resident inflammatory cell phenotypes, and may promote a profibrogenic DR and further infiltration of inflamed portal tracts. "
“We read with interest the review by Martínez et al.