Neuronal Loss after Stroke Due to Microglial Phagocytosis of Stressed Neurons.

Guy C Brown

doi:10.3390/ijms222413442

Abstract

After stroke, there is a rapid necrosis of all cells in the infarct, followed by a delayed loss of neurons both in brain areas surrounding the infarct, known as ‘selective neuronal loss’, and in brain areas remote from, but connected to, the infarct, known as ‘secondary neurodegeneration’. Here we review evidence indicating that this delayed loss of neurons after stroke is mediated by the microglial phagocytosis of stressed neurons. After a stroke, neurons are stressed by ongoing ischemia, excitotoxicity and/or inflammation and are known to: (i) release “find-me” signals such as ATP, (ii) expose “eat-me” signals such as phosphatidylserine, and (iii) bind to opsonins, such as complement components C1q and C3b, inducing microglia to phagocytose such neurons. Blocking these factors on neurons, or their phagocytic receptors on microglia, can prevent delayed neuronal loss and behavioral deficits in rodent models of ischemic stroke. Phagocytic receptors on microglia may be attractive treatment targets to prevent delayed neuronal loss after stroke due to the microglial phagocytosis of stressed neurons.

Highlights

Stroke is an acute reduction in blood flow within the brain and a major cause of mortality and morbidity throughout the world [1]
There is evidence outlined above to suggest that microglial phagocytosis can be either protective or damaging after stroke (Figure 3)
This may vary with the severity of the insult, as neurons subjected to severe insults are unlikely to be rescued by inhibiting phagocytosis, and severe insults generate debris that needs to be cleared and remodeled by microglial phagocytosis

Summary

Introduction

Stroke is an acute reduction in blood flow within the brain and a major cause of mortality and morbidity throughout the world [1]. Stroke rapidly kills neurons in the brain areas of lowest blood flow, resulting in an infarct of necrotic brain tissue; but stroke induces the delayed death and loss of neurons in brain areas surrounding the infarct (the penumbra) or brain areas distant but neuronally connected to the infarct [2,3,4,5,6]. We review the evidence that this delayed neuronal death is due to the microglial phagocytosis of neurons and, may be prevented by blocking this phagocytosis. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations

Types of Neuronal Death after Stroke

Microglia and Microglial Phagocytosis of Neurons

Phagocytic Signaling in Stroke

Conclusions