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Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis.

ABSTRACT: Various pathophysiologic mechanisms leading to sickness behaviors have been proposed. For example, an inflammatory process in the hypothalamus has been implicated, but the signaling modalities that involve inflammatory mechanisms and neuronal circuit functions are ill-defined. Here, we show that toll-like receptor 2 (TLR2) activation by intracerebroventricular injection of its ligand, Pam3CSK4, triggered hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in altered input organization and increased activity of proopiomelanocortin (POMC) neurons. These animals developed sickness behavior symptoms, including anorexia, hypoactivity, and hyperthermia. Antagonists of nuclear factor kappa B (NF-?B), cyclooxygenase pathway and melanocortin receptors 3/4 reversed the anorexia and body weight loss induced by TLR2 activation. These results unmask an important role of TLR2 in the development of sickness behaviors via stimulation of hypothalamic microglia to promote POMC neuronal activation in association with hypothalamic inflammation.

SUBMITTER: Jin S

PROVIDER: S-EPMC4942617 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis.

Jin Sungho S Kim Jae Geun JG Park Jeong Woo JW Koch Marco M Horvath Tamas L TL Lee Byung Ju BJ

Scientific reports 20160712

Various pathophysiologic mechanisms leading to sickness behaviors have been proposed. For example, an inflammatory process in the hypothalamus has been implicated, but the signaling modalities that involve inflammatory mechanisms and neuronal circuit functions are ill-defined. Here, we show that toll-like receptor 2 (TLR2) activation by intracerebroventricular injection of its ligand, Pam3CSK4, triggered hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in altered ...[more]

PMID: 27405276

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Project description:Microglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-? (A?) in Alzheimer's disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD.Here, we investigated whether an antibody that targets toll-like receptor (TLR)2 might attenuate the inflammatory and metabolic changes induced by lipopolysaccharide (LPS) and amyloid-?. The impact on phagocytosis was assessed by immunohistochemistry. We evaluated the metabolic changes with the SeaHorse Extracellular Flux Analyser and studied the expression of key enzymes driving glycolysis by western blotting. For all experiments, statistical significance was determined by unpaired Student's t test and two-way analysis of variance (ANOVA).We have reported that, when exposed to an inflammatory stimulus, microglia switch their metabolism towards the metabolically- inefficient glycolysis; this potentially impacts on metabolically demanding functions like phagocytosis. Anti-TLR2 antibody increased phagocytosis of A? in LPS?+?A?-stimulated microglia and this was linked with the ability of the antibody to attenuate the LPS?+?A?-triggered inflammasome activation. LPS?+?A? increased glycolysis in microglia and increased the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3, an enzyme that plays a key role in driving glycolysis; these effects were inhibited when cells were incubated with the anti-TLR2 antibody. The data also show that antibody treatment increased oxidative metabolism.Thus, microglia with an inflammatory phenotype, specifically cells in which the inflammasome is activated, are glycolytic; this may compromise the metabolic efficiency of microglia and thereby provide an explanation for the reduced phagocytic function of the cells. We propose that, by restoring oxidative metabolism and reducing inflammasome activation in microglia, phagocytic function is also restored.

Dataset Information

Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis.

Publications

Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis.

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