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.
Highlights
INTRODUCTIONImpaired neuronal function [1,2,3,4], from neuroinflammation or other causes, is a known driver of depression and related neuropsychiatric problems [5,6,7,8,9,10,11] that often accompany complex CNS disorders, including TBI [12, 13] and CNS disorders with autoimmune components [14], such as multiple sclerosis (MS) [15, 16], Parkinson’s disease (PD) [17,18,19], and Pediatric Acuteonset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) [20]
Infection [73, 114, 115], stress and depression [6, 116,117,118], altered microbiota [120] and other forms of digestive dysregulation [119,120,121,122], dysglycemia, insulin resistance, and obesity [123,124,125,126], tissue hypoxia [80, 127, 128, 129], poor diet [130,131,132,133,134], lack of exercise [135,136,137,138,139], environmental or other toxic exposure [140,141,142,143,144], and autoimmune processes [145, 146] are all potential drivers of body inflammation. These factors may be worthy of attention in patients with neuropsychiatric disorders associated with neuroinflammation, patients with head trauma, neuroinflammation, or any condition known to be worsened by neuroinflammation and changes in microglial activation, including Parkinson’s disease (PD), Alzheimer’s disease (AD) or other dementias, ALS, multiple sclerosis (MS), and Pediatric Acuteonset Neuropsychiatric Syndrome (PANS)/PANDAS
The presence of depression and related neuropsychiatric phenomena in a patient may reflect the presence of an underlying neuroinflammatory state and/or other comorbidities that can affect neuron - microglial interactions, with consequences for neuronal loss and neuro-autoimmunity
Summary
Impaired neuronal function [1,2,3,4], from neuroinflammation or other causes, is a known driver of depression and related neuropsychiatric problems [5,6,7,8,9,10,11] that often accompany complex CNS disorders, including TBI [12, 13] and CNS disorders with autoimmune components [14], such as multiple sclerosis (MS) [15, 16], Parkinson’s disease (PD) [17,18,19], and Pediatric Acuteonset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) [20]. Galván describes the synaptic pruning that occurs in brain development and that of adults as occurring on a continuum [45] These are normal processes, in contrast with the excessive microglial phagocytosis of live neurons that is a primary effect of the altered neuron-microglial signaling with which this paper concerns itself [31]. At any age, microglial morphology can change, disrupting the healthy homeostatic balance between neurons and microglia, and leading to excessive neuroinflammation, triggering or promoting the progression of neuronal loss and brainbased autoimmune processes such as MS, PD, dementia, PANS/ PANDAS, and chronic traumatic encephalopathy (CTE) [56,57,58,59,60]
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