Exploring the role of the transferrin receptor 2 in intestinal inflammation

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

Iron plays a crucial role in chronic inflammatory processes where it serves as an essential energy source for both pathogens and immune cells. The regulation of iron availability is a key mechanism for hindering pathogen growth, often resulting in inadequate iron supply, subsequently compromising erythropoiesis. Transferrin receptor 2 (Tfr2) is a key regulator of systemic iron availability that on top also regulates bone homeostasis and erythropoiesis. Thus, in my initial grant application, I hypothesized that Tfr2 migth be an important player in mediating the inflammatory response in arthritis and subsequent bone loss. In fact, we could show that Tfr2 is implicated in the regulation of arthritis progression through the inhibition of macrophage polarization towards an M1-pro-inflammatory state. Building upon these findings, the central hypothesis of this proposal is that Tfr2 exhibits comparable effects in various other chronic inflammatory diseases, extending beyond arthritis. As inflammatory bowel diseases (IBD) also represents a group of chronic inflammatory diseases that is associated with an elevated risk for osteoporosis and fractures, and Tfr2 is also expressed in the intestine, we next plan to study the role of Tfr2 in colitis and subsequent bone loss. To address this, we will i) evaluate the contribution of Tfr2 and/or iron overload to intestinal inflammation in mouse models with a particular emphasis on the actions of macrophages and monocytes; ii) define the impact of intestinal inflammation on bone health; and iii) elucidate the molecular mechanisms through which Tfr2 influences the metabolic reprogramming of macrophages, contributing to the development of inflammation in the context of colitis. Collectively, this project aims to unravel novel insights into the role of Tfr2 in intestinal inflammation and may potentially contribute to the development of innovative strategies for treating various inflammatory disorders.

• DFG Programme: Research Grants