Aurreko ekintzak: Amanda Sierra. Not just corpse removal: how microglial phagocytosis maintains brain tissue homeostasis

From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells as well as protein aggregates. To eliminate excess, dysfunctional or aged cells without imposing alterations or damage in the surrounding cells, apoptotic cell death and microglial phagocytosis are evolutionarily linked together. In this talk we will first introduce the concept that phagocytosis is not merely passive corpse removal, but has an active role in maintaining tissue homeostasis. I will focus in the adult hippocampal neurogenic cascade, where most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Using a combination of genetic disruption of phagocytosis in vivo, and an in vitro model to study the transcriptional and metabolic changes in microglia after phagocytosis, we show that microglia is reprogrammed by phagocytosis to act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis. I will next focus on the role of microglia in diseases and show that when challenged with increased numbers of apoptotic cells, microglia plastically respond by increasing their phagocytic capacity, maintaining apoptosis and phagocytosis tightly coupled. However, microglial phagocytosis is chronically impaired in pathological conditions such as epilepsy and stroke, resulting in accumulation of apoptotic cells and inflammation. Because neuronal death and inflammation are hallmarks of all major brain diseases, such as ischemic stroke, Alzheimer´s, Parkinson´s, or Multiple Sclerosis, harnessing microglial phagocytosis may serve to control tissue damage and inflammation as a novel strategy to accelerate brain recovery.