Role of the transferrin receptor 2 (Tfr2) in the pathogenesis of inflammatory arthritis

• Applicant: Dr. Maria G. Ledesma Colunga, Ph.D.
• Subject Area: Rheumatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 469828455

Iron is a crucial determinant of chronic inflammatory processes as it is required as an energy source for pathogens and immune cells. In terms of host defense against invading pathogens, the body induces the expression of acute-phase proteins, such as hepcidin, which is a key regulator of iron homeostasis. By increasing hepcidin production, cellular iron export is inhibited, leading to low levels of circulating iron. This mechanism limits iron availability for pathogens, but also leads to insufficient iron supply that compromises erythropoiesis. Hence, anemia is a frequent complication of chronic inflammatory diseases. Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovium that leads to joint dysfunction and disability. Early studies have suggested a poorer clinical outcome if patients receiving iron supplementation to correct their anemia. In this study, we plan to investigate the role of the transferrin receptor 2 (Tfr2) in chronic inflammation, as it is a key upstream regulator of hepcidin and thus iron homeostasis. Recent data from our group have revealed that besides its iron regulatory function in the liver, Tfr2 is also expressed in bone cells and controls bone homeostasis. Moreover, preliminary data suggest a role of Tfr2 in the regulation of arthritis progression and macrophage polarization in vitro. Our central hypothesis is that by controlling cellular iron stores, Tfr2 regulates the extent of inflammation and thus, the extent of bioenergetic programming and polarization of macrophages. We will test our hypothesis by i) assessing the contribution of iron overload and/or Tfr2 deficiency in the development and progression of macrophage-dependent inflammatory diseases such as RA, and ii) defining the role of Tfr2 on energy metabolism beyond iron regulation. Taken together, this project will unravel novel and detailed insights into the role of Tfr2 in the pathogenesis of arthritis and will potentially foster the development of innovative strategies to treat inflammatory disorders.

• DFG Programme: Research Grants