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

Marquez-Ropero, M.; Valero, J.; Cuesta-Puente, X.; Marquez-Galera, A.; Pereira-Iglesias, M.; Gonzalez-Dominguez, M.; Louail, A.; Beccari, S.; Lopez-Murillo, L.; San Juan, A.; Arrey, G.; Diaz-Aparicio, I.; Dubbelaar, M. L.; Ribera-Ramos, A.; Sarmiento Soto, M.; Ruiz, R.; Ayerra, L.; Vilas-Zornoza, A.; Cabrera, D.; van Liempd, S.; Garcia-Moreno, F.; Blomgren, K.; Gonzalez-Granero, S.; Garcia-Verdugo, J. M.; Falcon-Perez, J. M.; Aymerich, M. S.; Hambardzumyan, D.; Casafont, I.; Eggen, B. J. L.; Venero, J. L.; Lopez-Atalaya, J. P.; Sierra, A.

doi:10.1101/2025.09.18.676800

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bioRxiv · 10.1101/2025.09.18.676800

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

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Abstract

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.

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Marquez-Ropero, M., Valero, J., Cuesta-Puente, X., Marquez-Galera, A., Pereira-Iglesias, M., Gonzalez-Dominguez, M., Louail, A., Beccari, S., Lopez-Murillo, L., San Juan, A., Arrey, G., Diaz-Aparicio, I., Dubbelaar, M. L., Ribera-Ramos, A., Sarmiento Soto, M., Ruiz, R., Ayerra, L., Vilas-Zornoza, A., Cabrera, D., van Liempd, S., Garcia-Moreno, F., Blomgren, K., Gonzalez-Granero, S., Garcia-Verdugo, J. M., Falcon-Perez, J. M., Aymerich, M. S., Hambardzumyan, D., Casafont, I., Eggen, B. J. L., Venero, J. L., Lopez-Atalaya, J. P., Sierra, A.. 2025-09-19. Metabolic and transcriptional adaptations to phagocytosis in microglia sustain their functionality and regenerative properties. https://doi.org/10.1101/2025.09.18.676800

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