title: Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve.
abstract: Systemic infection can initiate or exacerbate central nervous system (CNS) pathology, even in the absence of overt invasion of bacteria into the CNS. Recent epidemiological studies have demonstrated that human survivors of sepsis have an increased risk of long-term neurocognitive decline. There is thus a need for improved understanding of the physiological mechanisms whereby acute sepsis affects the CNS. In particular, MyD88-dependent activation of brain microvascular endothelial cells and a resulting loss of blood-brain barrier integrity have been proposed to play an important role in the effects of systemic inflammation on the CNS. Signaling through the vagus nerve has also been considered to be an important component of CNS responses to systemic infection. Here, we demonstrate that blood-brain barrier permeabilization and hippocampal transcriptional responses during polymicrobial sepsis occur even in the absence of MyD88-dependent signaling in cerebrovascular endothelial cells. We further demonstrate that these transcriptional responses can occur without vagus nerve input. These results suggest that redundant signals mediate CNS responses in sepsis. Either endothelial or vagus nerve activation may be individually sufficient to transmit systemic inflammation to the central nervous system. Transcriptional activation in the forebrain in sepsis may be mediated by MyD88-independent endothelial mechanisms or by non-vagal neuronal pathways.
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Honig
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Simone
authors.initials: S
authors.lastname: Mader
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Huiyi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Amit
authors.initials: A
authors.lastname: Porat
authors.affiliation: Center for Translational Research, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.affiliation: Center for Translational Research, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Volpe
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D060085:Coinfection / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014630:Vagus Nerve / Q000378:metabolism*
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88