Decoding the Role of Resident Tissue Macrophages in Controlling Local Iron Levels and Supporting Organ Function 2309623

Abstract Introduction Iron is an essential micronutrient for nearly all organisms, yet how its balance and distribution are maintained at the tissue level remains poorly understood. We propose that vasculature-associated macrophages (VAMs), a specialized population of resident macrophages, centrally regulate iron homeostasis within adipose tissue. Although traditionally associated with host defense, resident macrophages–including VAMs–likely perform important non-immune functions that are not yet fully appreciated. Gene expression profiling reveals that VAMs possess the full molecular machinery for iron import, export, processing, and storage. These findings support our hypothesis that VAMs act as key regulators of adipose tissue iron content, sensing local metabolic demand and adjusting iron availability to maintain tissue homeostasis. Methods We use macrophage-specific mouse models, along with flow cytometry, confocal imaging, inductively coupled plasma mass spectrometry, and physiological stimuli that induce lipolysis and thermogenesis in visceral adipose tissue. Results Our preliminary data indicate that VAMs are the most efficient adipose tissue cell type for importing transferrin-bound iron from the circulation and serve as major intracellular iron reservoirs. When adipose tissue undergoes high bioenergetic activity, VAMs increase their uptake of transferrin-bound iron and enhance iron mobilization to support elevated tissue demands. Conversely, disrupting iron storage in VAMs reduces iron availability to neighboring stromal cells and diminishes their capacity to activate during energetically demanding processes such as lipolysis. Conclusion This work expands our understanding of how the immune system contributes to tissue physiology beyond classical host defense, specifically by defining the mechanistic roles of resident tissue macrophages in upholding iron homeostasis at tissue level. Funding Source Howard Hughes Medical Institute Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)