title: P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors.
abstract: Sickness behaviors, such as fatigue, mood alterations, and cognitive dysfunction, which result from changes in central neurotransmission, are prevalent in systemic inflammatory diseases and greatly impact patient quality of life. Although, microglia (resident cerebral immune cells) and cytokines (e.g., TNFα) are associated with changes in central neurotransmission, the link between peripheral organ inflammation, circulating cytokine signaling, and microglial activation remains poorly understood. Here we demonstrate, using cerebral intravital microscopy, that in response to liver inflammation, there is increased monocyte specific rolling and adhesion along cerebral endothelial cells (CECs). Peripheral TNFα-TNFR1 signaling and the adhesion molecule P-selectin are central mediators of these monocyte-CEC adhesive interactions which were found to be closely associated with microglial activation, decreased central neural excitability and sickness behavior development. Similar monocyte-CEC adhesive interactions were also observed in another mouse model of peripheral organ inflammation (i.e., 2,4-dinitrobenzene sulfonic acid-induced colitis). Our observations provide a clear link between peripheral organ inflammation and cerebral changes that impact behavior, which can potentially allow for novel therapeutic interventions in patients with systemic inflammatory diseases.
authors.affiliation: Immunology Research Group and Gastrointestinal Research Group, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, and Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Charlotte
authors.initials: C
authors.lastname: D'Mello
authors.forename: Kiarash
authors.initials: K
authors.lastname: Riazi
authors.forename: Tai
authors.initials: T
authors.lastname: Le
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Stevens
authors.forename: Arthur
authors.initials: A
authors.lastname: Wang
authors.forename: Derek M
authors.initials: DM
authors.lastname: McKay
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Pittman
authors.forename: Mark G
authors.initials: MG
authors.lastname: Swain
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D002540:Cerebral Cortex / Q000473:pathology*; D002779:Cholestasis / Q000150:complications / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives / Q000633:toxicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D055809:Illness Behavior / Q000502:physiology*; D007249:Inflammation / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism*; D009113:Muramidase / Q000235:genetics; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000633:toxicity
chemical_list: D016207:Cytokines; D019007:P-Selectin; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene; D000410:Alanine Transaminase; D009113:Muramidase; D010433:Pentylenetetrazole
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