Microglial Corpse Clearance: Lessons From Macrophages

Abstract

From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells and protein aggregates. To prevent garbage buildup, the brain is equipped with efficient phagocytes: the microglia. Microglia are similar, but not identical to other tissue macrophages, and in this review, we will first summarize the differences in the origin, lineage and population maintenance of microglia and macrophages. Then, we will discuss several principles that govern macrophage phagocytosis of apoptotic cells (efferocytosis), including the existence of redundant recognition mechanisms ("find-me" and "eat-me") that lead to a tight coupling between apoptosis and phagocytosis. We will then describe that resulting from engulfment and degradation of apoptotic cargo, phagocytes undergo an epigenetic, transcriptional and metabolic rewiring that leads to trained immunity, and discuss its relevance for microglia and brain function. In summary, we will show that neuroimmunologists can learn many lessons from the well-developed field of macrophage phagocytosis biology.

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

“…> 100 kD) [104]. With regard to intact RBCs, erythrophagocytosis by microglia [105] is usually insufficient to prevent free hemoglobin release and neurotoxicity. Similar to myoglobin in muscles, neuroglobin is a reserve form of hemoprotein able to store oxygen and protect the brain, at least in part, from hypoxic/ischemic insults [106].…”

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

“…Interestingly, cFos active neurons, The close relationship between apoptotic cells and active neurons in Cstb KO mice is supported by both direct measurements and the virtual 3D model but does not provide evidence that this relationship affects phagocytosis. Nonetheless, it is important to note that the net apoptosis observed is in part the result of the phagocytosis dynamics: the number of apoptotic cells at any given time depends as much on the input (apoptosis induction) as on the output (removal by phagocytosis) 14 . Therefore, our data shows an overall impairment of microglial phagocytosis in the GL of Cstb KO mice and suggests a complex scenario in which sub-seizure local neuronal activity may affect the clearance of apoptotic cells by microglia.…”

“…In addition, Cstb KO mice present early alterations in the inflammatory response of microglia, the brain immune cells [11][12][13] . In addition to controlling the release of inflammatory mediators, microglia are also the brain professional macrophages 14 . We have recently reported that in both mouse and human mesial temporal lobe epilepsy (MTLE), microglial phagocytosis of apoptotic cells is impaired 15 , leading us to question whether the phagocytosis impairment would also occur in Cstb KO mice.…”

“…Phagocytosis is a highly regulated response that prevents the spillover of cytotoxic content that results from the cell death, is immunomodulatory, and actively participates in maintaining tissue homeostasis 14,16,17 . In physiological conditions, microglia are very efficient phagocytes, as their processes constantly scan the brain parenchyma and express a plethora of receptors for "find-me" and "eat-me" signals produced by apoptotic cells [18][19][20][21] .…”

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

“…Phagocytosis is a highly regulated response that prevents the spillover of cytotoxic content that results from the cell death, is immunomodulatory, and actively participates in maintaining tissue homeostasis. 14,16,17 In physiological conditions, microglia are very efficient phagocytes, as their processes constantly scan the brain parenchyma and express a plethora of receptors for "find-me" and "eat-me" signals produced by apoptotic cells. [18][19][20][21] Microglia are similarly efficient facing increased apoptotic cell numbers generated during excitotoxicity and inflammation, as they use several strategies to cope with increased apoptosis: (1) recruit more phagocytic cells, (2) increase the number of apoptotic cells phagocytosed per microglial cell, and/or (3) increase the microglial numbers.…”