Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice

Lijian Wang, et al. J. Clin. Invest. 119:3322–3328 (2009)

Speaker: 連國廷                                           Time: 15:00~16:00, April 07, 2010

Commentator: 劉清泉 醫師                       Place: Room 601

Abstract:

Hereditary hemochromatosis (HH) is an inherited disorder characterized by increased iron absorption from the gut. The most common form of this disease, type I HH, is caused by mutations in Hfe, the hemochromatosis gene that encodes an atypical class I MHC protein expressed on hepatocytes, macrophages, and intestinal crypt cells [1]. The function of the HFE protein is to sense circulating iron status and initiate the expression of hepcidin. Hepcidin is a secreted hepatocyte peptide that could bind to the ferroportin (FPN), an iron export protein expressed on the surface of macrophages and duodenal enterocytes, and induce its internalization and degradation. Hepcidin production increases with iron load and inflammation, and decreases with iron deficiency, anemia, and hypoxia. The expression of FPN is elevated in patients of type I HH or Hfe^-/- mice which can cause increased iron absorption from the gut and iron release from phagocytes that lead to the  pathologic deposition of metal in various tissues. It has been previously shown that the production of two proinflammatory cytokines, TNF-α and IL-6, was significantly decreased in Hfe^-/- peritonealmacrophages after Salmonella infection or LPS treatment [2]. In this study, the authors showed that the abnormal TNF-α production in Hfe^-/- peritoneal macrophages was mediated by Toll-like receptor (TLR) 4, but not TLR 2. In addition, the production of IFN-β, a response mediated by TRAM/TRIF signaling pathway, was decreased in Hfe^-/- peritoneal macrophages after LPS treatment, suggesting that the TRAM/TRIF-dependent responses activated by TLR4 maybe impaired in Hfe^-/- peritoneal macrophages. In a previous study, the authors also showed that the free intracellular iron in Hfe^-/- peritoneal macrophages was decreased as a result of elevated FPN expression. To determine the role of free intracellular iron on the production of proinflammatory cytokines by macrophages, they treated the wild-type macrophages with iron chelator, and found that the production of IFN-β in macrophages after LPS stimulation was decreased. On the other hand, the wild-type mice treated with hepcidin inhibitors, which blocked the bone morphogenetic protein (BMP) receptor–activated signals required for hepcidin upregulation in response to inflammatory stimuli, resulted in decreased expression of TNF-α and IL-6 in ceca and colon, respectively. These results suggest that the altered iron homeostasis may play an important role in modulating the proinflammatory cytokine expression in mice.

References:

1.      Feder, J.N., et al. 1996. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet. 13:399–408.

2.      Wang, L., et al. 2008. Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J. Immunol. 181:2723–2731.