title: 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-κB), 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.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Republic of Korea.
authors.forename: Sungho
authors.initials: S
authors.lastname: Jin
authors.affiliation: Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon, 406-772, Republic of Korea.|Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jae Geun
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Republic of Korea.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.|Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Koch
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Republic of Korea.
authors.forename: Byung Ju
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000855:Anorexia / Q000473:pathology*; D001111:Arcuate Nucleus of Hypothalamus / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology; D005334:Fever / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D055666:Lipopeptides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051381:Rats; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
chemical_list: D016861:Cyclooxygenase Inhibitors; D055666:Lipopeptides; C574273:MC4R protein, mouse; C470053:Mc3r protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C508075:Pam(3)CSK(4) peptide; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D011333:Pro-Opiomelanocortin