title: Microglial recruitment of IL-1β-producing monocytes to brain endothelium causes stress-induced anxiety.
abstract: Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1+neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1KOspecifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: McKim
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Weber
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Niraula
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Sawicki
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Jarrett
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ramirez-Chan
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Roeth
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Sucaldito
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Sobol
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.|Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: N
authors.initials: N
authors.lastname: Quan
authors.affiliation: Division of Biosciences, The Ohio State University College of Dentistry, Columbus, OH, USA.|Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Sheridan
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA.|Institute for Behavioral Medicine Research, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Godbout
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism*; D001008:Anxiety Disorders / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta