Elucidating the Role of Iron-Handling Macrophages in Adipose Tissue

Abstract

The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron handling genes. While studies have demonstrated iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence AT iron availability. Two methodologies were used to address this question – dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, while the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron cycling expression profile. The iron injection model was also incorporated into a model of high-fat diet induced obesity. In these studies, obesity did not impede the ability of MFehi to take up excess iron. Lastly, we explored the use of liposomes and micelle nanoparticles for target ATMs in a cell- and tissue-specific manner. Preliminary findings demonstrated that these new technologies show promise as methods to deplete MFehi or modulate their ability to handle iron. The studies detailed in this dissertation expand upon the field’s understanding of ATMs and demonstrate that they can respond as a tissue iron sink in models of iron overload.