Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
Phagocytosis by microglia is tightly coupled to apoptosis, swiftly removing apoptotic cells and actively maintaining tissue homeostasis, but the neuronal hyperactivity associated with epilepsy disrupts the ATP gradients that drive phagocytosis, leading to the accumulation of apoptotic cells and inflammation.
Author Summary Phagocytosis, the engulfment and digestion of cellular debris, is at the core of the regenerative response of the damaged tissue, because it prevents the spillover of toxic intracellular contents and is actively anti-inflammatory. In the brain, the professional phagocytes are microglia, whose dynamic processes rapidly engulf and degrade cells undergoing apoptosis—programmed cell death—in physiological conditions. Thus, microglia hold the key to brain regeneration, but their efficiency as phagocytes in the diseased brain is only presumed. Here, we have discovered a generalized response of microglia to apoptotic challenge induced by excitotoxicity and inflammation, in which they boost their phagocytic efficiency to account for the increase in apoptosis. To our surprise, this apoptosis/microglial phagocytosis coupling was lost in the hippocampus from human and experimental mesial temporal lobe epilepsy (MTLE), a major neurodegenerative disorder characterized by excitotoxicity, inflammation, and seizures. This uncoupling was due to widespread ATP release during neuronal hyperactivity, which “blinded” microglia to the ATP microgradients released by apoptotic cells as “find-me” signals. The impairment of phagocytosis led to the accumulation of apoptotic cells and the build-up of a detrimental inflammatory reaction. Our data advocates for systematic assessment of the efficiency of microglial phagocytosis in brain disorders.