Abstract
We have recently reported that Kupffer cells consist of two subsets, radio-resistant resident CD68+ Kupffer cells and radio-sensitive recruited CD11b+ Kupffer cells/macrophages (Mφs). Non-alcoholic steatohepatitis (NASH) is characterized not only by hepatic steatosis but also chronic inflammation and fibrosis. In the present study, we investigated the immunological mechanism of diet-induced steatohepatitis in fibroblast growth factor 5 (FGF5) deficient mice. After consumption of a high fat diet (HFD) for 8 weeks, FGF5 null mice developed severe steatohepatitis and fibrosis resembling human NASH. F4/80+ Mφs which were both CD11b and CD68 positive accumulated in the liver. The production of TNF and FasL indicated that they are the pivotal effectors in this hepatitis. The weak phagocytic activity and lack of CRIg mRNA suggested that they were recruited Mφs. Intermittent exposure to 1 Gy irradiation markedly decreased these Mφs and dramatically inhibited liver inflammation without attenuating steatosis. However, depletion of the resident subset by clodronate liposome (c-lipo) treatment increased the Mφs and tended to exacerbate disease progression. Recruited CD11b+ CD68+ Kupffer cells/Mφs may play an essential role in steatohepatitis and fibrosis in FGF5 null mice fed with a HFD. Recruitment and activation of bone marrow derived Mφs is the key factor to develop steatohepatitis from simple steatosis.
Highlights
wild type (WT) CD WT high fat diet (HFD) long hair (LH) CD LH mice fed the HFD (LH HFD) different; the former has a phagocytic and bactericidal function and the latter population plays a critical role in hepatic inflammation by secreting proinflammatory cytokines[13], which may be the case in Kupffer cells in humans[13]
Severe hepatic injury was observed in LH mice fed the HFD (LH HFD) for 8 weeks but not in LH mice fed control diet (LH CD) as previously reported (Fig. 1A)[21]
In LH HFD mice, hepatic steatosis and inflammatory cell infiltration was observed in portal area (Fig. 2D)
Summary
WT CD WT HFD LH CD LH HFD different; the former has a phagocytic and bactericidal function and the latter population plays a critical role in hepatic inflammation by secreting proinflammatory cytokines[13], which may be the case in Kupffer cells in humans[13]. Based on our research and other reports dealing with human subjects, the CD11b population seems to play a pivotal role in the induction of inflammation and fibrosis in the pathogenesis of NASH14–16. Some studies have reported that the single nucleotide mutation (polymorphism) of this gene is associated with hypertension in humans[22,23,24,25]. We have reported that a high fat diet (HFD) increased non-HDL cholesterol levels in FGF5 null LH mice and induced steatohepatitis resembling human NASH21. In the present study, based on our recent subclassification of Kupffer cell phenotypes, we investigated the immunological mechanism of this experimental model of NASH
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