Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo

Abstract

Cell death is prevalent throughout life; however, the coordinated interactions and roles of phagocytes during corpse removal in the live brain are poorly understood. We developed photochemical and viral methodologies to induce death in single cells and combined this with intravital optical imaging. This approach allowed us to track multicellular phagocytic interactions with precise spatiotemporal resolution. Astrocytes and microglia engaged with dying neurons in an orchestrated and synchronized fashion. Each glial cell played specialized roles: Astrocyte processes rapidly polarized and engulfed numerous small dendritic apoptotic bodies, while microglia migrated and engulfed the soma and apical dendrites. The relative involvement and phagocytic specialization of each glial cell was plastic and controlled by the receptor tyrosine kinase Mertk. In aging, there was a marked delay in apoptotic cell removal. Thus, a precisely orchestrated response and cross-talk between glial cells during corpse removal may be critical for maintaining brain homeostasis.

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

“…DAMP stimulation of PRRs on microglia, such as CR3 and toll-like receptor 4 (TLR4), mediates activation of pro-inflammatory signalling transducers NLRP3 inflammasome, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and mitogen-activated protein kinases (MAPKs), such as ERK [ 86 , 91 , 92 ]. Considering CR3 signalling is an essential functional component in synaptic pruning by microglia [ 93 ], NOX activation by PRRs is likely a functional inflammatory-related phagocytic response to eliminate dead and dying neurons and aggregated protein, which has been elucidated by 2-photon live imaging [ 94 , 95 ]. Hence, DAMP signalling on these receptors may underpin excessive ROS production by inflammatory-related phagocytic activation and prime a vicious cycle of DAMP-induced neuronal damage by oxidative stress [ 86 , 96 ] ( Figure 2 ).…”

Reactivity and increased proliferation of NG2 cells following central nervous system infection with Theiler’s murine encephalomyelitis virus

“…All images are ×20 maximum-intensity projections of 12 μm confocal z stacks. Scale bars = 100 μm microglia, astrocytes, and NG2 cells coordinate their response to clear damaged and dying neurons, with NG2 cells not only polarizing toward dying neurons but remaining to fill the lesion after removal of neuronal debris was complete [51]. While the exact purpose of NG2 cell activity in the formation of the glial scar remains unclear, increased expression, or deposits of NG2, otherwise known as chondroitin sulfate proteoglycan 4 (CSPG4), may form a barrier to repair damage in epilepsy-inducing lesions and significantly alter the function of surviving neurons and astrocytes, contributing to epileptogenesis [18].…”

The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

“…For example, the production of MFGE8 by astrocytes aids the phagocytosis and clearance of prion-infected and apoptotic neurons by microglia in some mouse strains [ 162 ]. However, it is important to note that reactive astrocytes are also capable of phagocytosing apoptotic neurons [ 205 ], challenging the conclusion that the phagocytosis and clearance of prions in the brain is restricted to the microglia [ 159 , 160 ]. Unlike the microglia [ 154 ], astrocytes may also be important sources of prion replication in the brain [ 206 ].…”