Microglial Phagocytosis of Neurons: Diminishing Neuronal Loss in Traumatic, Infectious, Inflammatory, and Autoimmune CNS Disorders

Abstract

Errors in neuron-microglial interaction are known to lead to microglial phagocytosis of live neurons and excessive neuronal loss, potentially yielding poorer clinical outcomes. Factors that affect neuron-microglial interaction have the potential to influence the error rate. Clinical comorbidities that unfavorably impact neuron-microglial interaction may promote a higher rate of neuronal loss, to the detriment of patient outcome. This paper proposes that many common, clinically modifiable comorbidities have a common thread, in that they all influence neuron-microglial interactions. Comorbidities like traumatic brain injury, infection, stress, neuroinflammation, loss of neuronal metabolic integrity, poor growth factor status, and other factors, all have the potential to alter communication between neurons and microglia. When this occurs, microglial phagocytosis of live neurons can increase. In addition, microglia can shift into a morphological form in which they express major histocompatibility complex II (MHC-II), allowing them to function as antigen presenting cells that present neuronal debris as antigen to invading T cells. This can increase risk for the development of CNS autoimmunity, or can exacerbate existing CNS autoimmunity. The detrimental influence of these comorbidities has the potential to contribute to the mosaic of factors that determine patient outcome in some CNS pathologies that have neuropsychiatric involvement, including TBI and CNS disorders with autoimmune components, where excessive neuronal loss can yield poorer clinical outcomes. Recognition of the impact of these comorbidities may contribute to an understanding of the common clinical observation that many seemingly disparate factors contribute to the overall picture of case management and clinical outcome in these complex disorders. In a clinical setting, knowing how these comorbidities can influence neuron-microglial interaction can help focus surveillance and care on a broader group of potential therapeutic targets. Accordingly, an interest in the mechanisms underlying the influence of these factors on neuron-microglial interactions is appropriate. Neuron-microglial interaction is reviewed, and the various mechanisms by which these potential comorbidities influence neuro-microglial interaction are described.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives

“…However, activation of microglial cells following viral infection in the CNS can also have deleterious effects as we previously showed ( Amorim et al., 2019 ; Salomão et al., 2020 ). Although both in physiological and pathological contexts, microglial cells are supposed to support neuronal development and survival and clear debris and dysfunctional synapses ( Tremblay et al., 2011 ; Yanuck, 2019 ), when overactivated during viral or bacterial infection, those cells can directly induce neuronal damage ( Chen et al., 2010 ; Klein et al., 2019 ; Mukherjee et al., 2019 ; Trzeciak et al., 2019 ). Also, microglial overactivation can lead to indirect neuronal death by activating astrocytes ( Tremblay et al., 2011 ) or T lymphocytes ( Zimmermann et al., 2017 ; Garber et al., 2019 ), further contributing to neuronal degeneration after viral infection ( Fig.…”

Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances

“…Microglial activation is the major contributor to neuroinflammation [ 46 ]. A range of stimuli, including infection, trauma, toxic insults, and ischemia, may initiate microglial activation and disrupt the central nervous system (CNS) homeostasis [ 47 , 48 ]. Once activated, microglia released pro-inflammatory and neurotoxic elements, like chemokines, cytokines, proteases, eicosanoids, ROS, and excitatory amino acids [ 47 ].…”

“…A range of stimuli, including infection, trauma, toxic insults, and ischemia, may initiate microglial activation and disrupt the central nervous system (CNS) homeostasis [ 47 , 48 ]. Once activated, microglia released pro-inflammatory and neurotoxic elements, like chemokines, cytokines, proteases, eicosanoids, ROS, and excitatory amino acids [ 47 ]. All of these elements are documented as a key player in neuroinflammation-associated OS as well as chronic neurodegeneration [ 49 ].…”

Leucine rich repeats and calponin homology domain containing 1 inhibits microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model

“…Previous research indicates that activated microglia induce neuronal death [22][23][24][25]. To test if LRCH1 is crucial for this process, we co-cultured unprimed or primed microglia with the N27 rat dopaminergic neural cell line in Transwell 96-well plates for 24 hours.…”