Redox in macrophages · Adaptive redox regulation in inflammatory macrophages

Adaptive redox regulation in inflammatory macrophages

Macrophages are an essential part of the innate immune system. Macrophages have diverse function that include clearing billions of dead cells each day, identifying and killing invading pathogens and initiating and terminating immune responses. They are first responders to pathogens, but also detect and eliminate cancer cells and maintain homeostasis by orchestrating the temporal progression of the wound healing response. We know now that macrophage functions are dictated by their underlying metabolic programs and metabolic adaptability that frequently center on electron transfer reactions (i.e., redox metabolism). For example, macrophages oxidize arginine to generate nitric oxide for pathogen defense; re-routing arginine for this purpose causes substantial changes to overall amino acid metabolism not observed in other cell types. Importantly, the cellular balance of redox reactions is particularly important to prevent cell death by ferroptosis. Ferroptosis is triggered by the accumulation of free Fe2+ iron and excessive free radicals (e.g., as needed for pathogen killing), leading to peroxidation of lipids in the cell membrane and ultimately cell death. Several antioxidant systems work in combination to clear free radicals and thus prevent ferroptosis. These include the glutathione pathway as well as glutathione independent biopterin and ubiquinone pathways and extracellular production of indoles from amino acids. While these redox pathways were discovered in cancer cells, their function and regulation in macrophages (which are major producers of free radicals) was unknown at the start of this project. To address this knowledge gap, this MSCA project used reduced complexity in vitro models of macrophage activation states to answer a) which molecular pathways regulate redox adaptation in different macrophage activation states (i.e. inflammatory, chronic-inflammatory, homeostatic) and b) how macrophages can rewire their redox systems in activation compared to homeostasis.

Data: CORDIS, © European Union