Abstract
Inflammation is increasingly recognized as a contributor to the pathophysiology of neuropsychiatric disorders, including depression, anxiety disorders and autism, though the factors leading to contextually inappropriate or sustained inflammation in pathological conditions are yet to be elucidated. Microglia, as the key mediators of inflammation in the CNS, serve as likely candidates in initiating pathological inflammation and as an ideal point of therapeutic intervention. Glucose deprivation, as a component of the pathophysiology of ischemia or occurring transiently in diabetes, may serve to modify microglial function contributing to inflammatory injury. To this end, primary microglia were cultured from postnatal rat brain and subject to glucose deprivation in vitro. Microglia were characterized for their proliferation, phagocytic function and secretion of inflammatory factors, and tested for their capacity to respond to a potent inflammatory stimulus. In the absence of glucose, microglia remained capable of proliferation, phagocytosis and inflammatory activation and showed increased release of inflammatory factors after presentation of an inflammatory stimulus. Glucose-deprived microglia demonstrated increased phagocytic activity and decreased accumulation of lipids in lipid droplets over a 48-h timecourse, suggesting they may use scavenged lipids as a key alternate energy source during metabolic stress. In the present manuscript, we present novel findings that glucose deprivation may sensitize microglial release of inflammatory mediators and prime microglial functions for both survival and inflammatory roles, which may contribute to psychiatric comorbidities of ischemia, diabetes and/or metabolic disorder.
Highlights
Inflammation of the central nervous system, regulated by microglia—the resident immune cells, is an acute reaction to the presence of infectious agents, foreign bodies or tissue damage intended to protect, contain and repair vulnerable CNS tissues
We present novel findings that glucose deprivation may sensitize microglial release of inflammatory mediators and prime microglial functions for both survival and inflammatory roles, which may contribute to psychiatric comorbidities of ischemia, diabetes and/or metabolic disorder
Given the correlation between ischemia/hypoglycemia and psychiatric disorders and lack of available evidence, we proposed the following question: what effect does the availability of glucose have on the initiation of inflammation in the CNS? As pro-inflammatory functions of microglia are energy intensive, requiring new protein synthesis and extensive cytoskeletal reorganization, it is perhaps unsurprising that treatment with inflammatory stimuli such as LPS and IFN-γ results in increased glucose uptake and utilization [92, 93] and result in distinct metabolic changes to support such vital functions [94]
Summary
Inflammation of the central nervous system, regulated by microglia—the resident immune cells, is an acute reaction to the presence of infectious agents, foreign bodies or tissue damage intended to protect, contain and repair vulnerable CNS tissues. A recently popularized hypothesis postulates the aetiology of depression may derive, in part, from prolonged or chronic immune activation [15, 27, 28] Consistent with this hypothesis, a number of studies have found elevated peripheral cytokines ( tumour necrosis factor (TNF) and interleukin-6 (IL-6)) in depressed patients, and depression is the most observed psychiatric comorbidity of medical illness [29]. By extension, observed increases in inflammatory markers in otherwise medically healthy depressed patients suggests depression, in some cases, may result from maladaptive expression of sickness behaviours in the absence of infection or illness Such observations in psychiatric and neurological disease has led to recent understanding that inflammation is a key component of the pathophysiology of many neurological, neurodegenerative and neuropsychiatric disorders, and is encouraging research into the mechanisms underlying inflammatory processes in the CNS [18]
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