Biology subjects

Diaz-Aparicio, I.

Publications and source records attributed to Diaz-Aparicio, I..

3 recordsLinked to original sources

bioRxiv2025

Metabolic and transcriptional adaptations to phagocytosis in microglia sustain their functionality and regenerative properties

Phagocytosis of apoptotic cells, or efferocytosis, is a tightly regulated process that ensures tissue homeostasis and prevents mounting inflammatory responses. In the brain parenchyma, it is executed by microglia, which are encumbered by large numbers of apoptotic debris generated during development, in adult neurogenic niches, aging, and brain diseases. Emerging evidence suggest that phagocytosis is not limited to garbage disposal, but triggers adaptations in the phagocytes that may have a functional impact. To test it we developed an in vivo model of superphagocytosis induced by low cranial irradiation (LCI, 2Gy) that specifically induced apoptosis in the neurogenic niche of the adult hippocampus, synchronizing microglia in a phagocytic state within 6h and leading to full clearance by 24h. Single cell RNA sequencing and metabolomics revealed an unexpected oxidative stress in post-phagocytic microglia, accompanied by catabolic shutdown, mitochondrial remodeling, increased expression of galectin 3, and production of polyamines that led to cell death and compensatory proliferation. To test whether these changes impaired subsequent microglial phagocytosis, we used a glioblastoma model treated with sequential irradiation to induce tumor cell apoptosis. The phagocytosis efficiency of tumor-associated microglia/macrophages was comparable in the first and second apoptotic challenge, suggesting that the metabolic remodeling induced by phagocytosis was adaptive and destined to sustain their functionality. Finally, we assessed the functional impact of post-phagocytosis adaptations using galectin 3 deficient mice under LCI. We found that the recovery of the neurogenic niche after LCI strongly depended on galectin 3, demonstrating the regenerative capacity of post-phagocytic microglia. Overall, our data unveils the complexity of post-phagocytosis adaptations in microglia, underscoring their unexplored therapeutic potential in brain disorders.

neuroscience↗

bioRxiv2020

Microglial phagocytosis dysfunction is related to local neuronal activity in a genetic model of epilepsy

Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response in neurodegenerative diseases. Phagocytosis is very efficient in physiological conditions, as well as during apoptotic challenge induced by excitotoxicity or inflammation, but is impaired in mouse and human mesial temporal lobe epilepsy (MTLE). Here we extend our studies to a genetic model of progressive myoclonus epilepsy type 1 (EPM1) in mice lacking cystatin B (CSTB), an inhibitor of cysteine proteases involved in lysosomal proteolysis. We first demonstrated that microglial phagocytosis was impaired in the hippocampus in Cstb knock-out (KO) mice when seizures arise and hippocampal atrophy begins, at 1 month of age. To test if this blockage was related to the lack of Cstb in microglia, we used an in vitro model of phagocytosis and siRNAs to acutely reduce Cstb expression but we found no significant effect in the phagocytosis of apoptotic cells. We then tested whether seizures were involved in the phagocytosis impairment, similar to MTLE, and analyzed Cstb KO mice before seizures begin, at postnatal day 14. Here, phagocytosis impairment was restricted to the granule neuron layer but not to the subgranular zone, where there are no active neurons. Furthermore, we observed apoptotic cells (both phagocytosed and not phagocytosed) in Cstb deficient mice at close proximity to active, cFos+ neurons and used mathematical modeling to demonstrate that the physical relationship between apoptotic cells and cFos+ neurons was specific for Cstb KO mice. These results suggest a complex crosstalk between apoptosis, phagocytosis and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction in Cstb KO mice. Overall, this data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.

neuroscience↗

bioRxiv2019

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of their intracellular contents. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in mice chronically deficient for two microglial phagocytosis pathways (P2Y12 and MerTK/Axl), but was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of microglial phagocytosis in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia act as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.\n\nGRAPHICAL ABSTRACT

cell biology↗