Kupffer cell and interleukin-12-dependent loss of natural killer T cells in hepatosteatosis

Abstract

Background Hepatosteatosis is associated with increased expression of tumor necrosis factor alpha (TNFα) and interleukin (IL)-12, major T helper (Th) 1 cytokines, and reduced hepatic NKT cell numbers. The relationship between lipid accumulation, cytokine expression, and hepatic NKT cells is not known. This study was conducted to assess the role of IL-12 in the development of hepatic steatosis and its potential impact on liver NKT cells. Methods Male C57Bl/6 wild type (Wt) and IL-12-deficient (IL12−/−) mice were fed a choline deficient diet (CDD) for 0, 10 or 20 weeks. Findings CDD led to marked hepatosteatosis, reduced hepatic but not splenic NKT cell numbers and function and increased hepatic expression of the Th1-type cytokines IL-12, interferon gamma (IFNγ) and TNFα in wt mice. Absence of IL-12 resulted in similar CDD-induced hepatosteatosis, but preserved hepatic NKT cells and significantly reduced hepatic IFNγ and TNFα expression. Treatment of CDD fed mice with lipopolysaccharide led to a significant increase in hepatic IL12 expression and Kupffer cell (KC)_depletion reduced liver IL-12 expression and restored NKT cells in CDD-induced fatty liver. Interestingly, KCs from CDD fed mice failed to produce increased quantities of IL12 upon activation in vitro when compared to similarly treated KCs from control fed mice suggesting that secondary factors in vivo promote heightened IL-12 production. Finally, human livers with severe steatosis showed a substantial decrease in NKT and NK cells. Conclusions Hepatosteatosis reduces the numbers of hepatic NKT cells in a KC and IL-12-dependent manner. Our results suggest a pivotal and multi-functional role of KC-derived IL-12 in the altered immune response in steatotic liver, a process which is likely active within human non-alcoholic fatty liver disease.

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease

“…The mechanisms underpinning the decrease in NKT cells in NAFLD are still unknown. Since IL-12 has been shown to increase NKT cell activationinduced cell death (52), abnormal Kupffer cell activation due to increased LPS, with consequent increase in IL-12, has been proposed to play a role (25). Additional studies should be performed to evaluate whether the reduction in CD3 + cells is specific for NKT or more generalized, and whether, on the contrary, a selective increase in intralobular CD3 + cells is associated with the progression of liver disease.…”

“…The interaction between TLR-4 and endotoxin results in the release of a myriad of pro-inflammatory mediators which induce hepatic injury and fibrosis (24). Recently, Kremer et al (25) demonstrated that hepatosteatosis, in mice fed an MCD diet, is characterized at the hepatic level by an induction of interferon-γ and tumor necrosis factor-α, an elevated content of interleukin (IL)-12 and a remarkable reduction in the number and activity of NKT cells. The authors also highlighted that the reduction of the NKT cell population is due to the activation of Kupffer cells via an endotoxin-mediated mechanism.…”

Reply:

“…Syn and Oo for their interest in our recently published article in HEPATOLOGY. 1 Our data show an inverse correlation with the accumulation of lipid and the relative proportions and function of hepatic natural killer T (NKT) cells. 1 The model used for our studies was intentionally simple, absent of significant inflammation or tissue injury, and human samples were selected to mimic this pathology.…”

Inflammation hépatique liée à l’obésité (NASH)

“…On observe par ailleurs un profil pro-inflammatoire des cellules NKT presentes (Li et al, 2005). Une etude recente a montre que, chez l'homme, la diminution du nombre de lymphocytes NKT est egalement correlee avec le degre de steatose (Kremer et al, 2010).…”