Brain Region-Specific Alterations in the Gene Expression of Cytokines, Immune Cell Markers and Cholinergic System Components during Peripheral Endotoxin-Induced Inflammation

Molecular and Functional Neuroscience in Immunity

“…There is evidence that chronic peripheral immune activation and inflammation exacerbate neuroinflammation in neurodegenerative diseases, including Alzheimer disease (157) and schizophrenia (158, 159). Peripheral inflammatory stimuli, including LPS and live bacteria, can also cause proinflammatory signaling in the brain (160, 161). This proinflammatory signaling plays a role in mediating sickness behavior, associated with fever, reduced mobility, social withdrawal, and other symptoms, as demonstrated by peripheral administration of LPS, live bacteria, and cytokines, including TNF and IL-1β (44, 57, 161).…”

Neural circuitry and immunity

“…2). Increased systemic cytokine levels in endotoxemia are associated with activation in pro-inflammatory IL-1β and IL-6 gene expression and microglial morphological alterations, indicative for microglia activation as early as 4 hours following peripheral endotoxin administration [110]. These pro-inflammatory alterations affect the hippocampus, cortex, hypothalamus and other brain areas in a region-specific manner with no apparent evidence of neurodegeneration as an underlying event [110].…”

“…Increased systemic cytokine levels in endotoxemia are associated with activation in pro-inflammatory IL-1β and IL-6 gene expression and microglial morphological alterations, indicative for microglia activation as early as 4 hours following peripheral endotoxin administration [110]. These pro-inflammatory alterations affect the hippocampus, cortex, hypothalamus and other brain areas in a region-specific manner with no apparent evidence of neurodegeneration as an underlying event [110]. Excessive and non-resolved forms of peripheral inflammation and maladaptive transformations of sickness behavior can result in deleterious and life-threatening neurological complications described in several conditions with inflammatory and autoimmune etiology, including sepsis, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, postoperative conditions and obesity [23,69,111–119] (Fig.…”

Immunity-Based Evolutionary Interpretation of Diet-Induced Thermogenesis

“…LPS-related over-activation of the immune system also damages host tissues and contributes to the progression of obesity-related neurological and metabolic complications, including impaired cognitive functions, dysfunction and loss of pancreatic islet cells, insulin resistance, endothelial dysfunction, and atherosclerosis (Cani et al, 2012;Ehses et al, 2007;Lumeng and Saltiel, 2011;Pavlov and Tracey, 2015). Sustained chronic inflammation in endotoxemia is further exacerbated by the suppression of a vagally mediated anti-inflammatory pathway by LPS itself (Silverman et al, 2014). The vagally mediated anti-inflammatory pathway involves the release of acetylcholine from vagal efferents that inhibit pro-inflammatory cytokine secretion from macrophages in the reticuloendothelial system, including spleen, which among the organs contributes the most to pro-inflammtory cytokine elevation in endotoxemia (Tracey, 2002).…”

“…Integration of vagal afferent input and vagal efferent output occurs in the hindbrain (i.e., in the nucleus tractus solitarii, the area postrema, the dorsal motor nucleus of the vagus, and the nucleus ambiguous, areas which also receive input from and are modulated by the brain cholinergic system) (Pavlov and Tracey, 2015). Effects of peripheral LPS on the brain can be detected a few hours after intra-peritoneal injection of LPS into mice, including significant increases in transcriptional levels of pro-inflammatory cytokines in different parts of the brain, paralleled by altered expression of components in the brain cholinergic system (Silverman et al, 2014). Acetylcholinesterase inhibition has been shown to attenuate the chronic inflammation and associated metabolic sequelae related to DIO in animal models (Ali et al, 2015;Satapathy et al, 2011), indicating that an impaired cholinergic anti-inflammatory pathway contributes substantially to the pathogenesis of diet-induced metabolic dysregulation.…”