Seminar

Metabolic and transcriptional adaptations to apoptotic cell engulfment and degradation sustain long-term phagocytosis efficiency in microglia

Amanda Sierra

Phagocytosis is the first line of defense of the innate immune system to eliminate invading microbes and unwanted cell debris. Efferocytosis, or apoptotic cell phagocytosis, is a tightly regulated process that ensures tissue homeostasis and prevents mounting inflammatory responses. However, phagocytes suffer adaptations in response to the metabolic burden imposed by the ingested cargo. These adaptations are particularly critical in the brain, where microglia are encumbered by large numbers of apoptotic debris generated during development, in adult neurogenic niches, aging, and brain diseases. To test the functional impact of microglial phagocytosis we developed an in vivo model of “superphagocytosis” induced by low cranial irradiation (2Gy) that specifically induced apoptosis in the neurogenic niche of the adult hippocampus, synchronizing microglia in a phagocytic state by 6h and leading to full clearance by 24h. Using single cell RNA sequencing and metabolomics we discovered 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 model of glioblastoma treated with sequential irradiation to induce tumor cell apoptosis. Importantly, 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. This data uncovers a novel form of trained immunity in brain phagocytes induced by apoptotic cell phagocytosis with broad implications for the health of the brain parenchyma.