title: Circulating Monocytes Exhibit an Endotoxin Tolerance Status after Acute Ischemic Stroke: Mitochondrial DNA as a Putative Explanation for Poststroke Infections.
abstract: Patients with acute ischemic stroke (AIS) suffer from infections associated with mortality. The relevance of the innate immune system, and monocytes in particular, has emerged as an important factor in the evolution of these infections. The study enrolled 14 patients with AIS, without previous treatment, and 10 healthy controls. In the present study, we show that monocytes from patients with AIS exhibit a refractory state or endotoxin tolerance. The patients were unable to orchestrate an inflammatory response against LPS and expressed three factors reported to control the evolution of human monocytes into a refractory state: IL-1R-associated kinase-M, NFkB2/p100, and hypoxia-inducible factor-1α. The levels of circulating mitochondrial DNA (mtDNA) in patients with AIS correlated with impaired inflammatory response of isolated monocytes. Interestingly, the patients could be classified into two groups: those who were infected and those who were not, according to circulating mtDNA levels. This finding was validated in an independent cohort of 23 patients with AIS. Additionally, monocytes from healthy controls, cultured in the presence of both sera from patients and mtDNA, reproduced a refractory state after endotoxin challenge. This effect was negated by either a TLR9 antagonist or DNase treatment. The present data further extend our understanding of endotoxin tolerance implications in AIS. A putative role of mtDNA as a new biomarker of stroke-associated infections, and thus a clinical target for preventing poststroke infection, has also been identified.
authors.affiliation: Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-Jiménez
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gutierrez-Fernández
authors.affiliation: Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Cubillos-Zapata
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Otero-Ortega
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Rodríguez-Frutos
authors.affiliation: Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Toledano
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martínez-Sánchez
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Fuentes
authors.affiliation: Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: Aníbal
authors.initials: A
authors.lastname: Varela-Serrano
authors.affiliation: Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Avendaño-Ortiz
authors.affiliation: Mitochondrial Diseases Laboratory, University Hospital 12 de Octubre Research Institute, 28041 Madrid, Spain; and.|Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Blázquez
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Mangas-Guijarro
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute and Autonomous University of Madrid, 28049 Madrid, Spain.
authors.forename: Exuperio
authors.identifier: 0000-0003-2295-1707
authors.initials: E
authors.lastname: Díez-Tejedor
authors.affiliation: Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain; elopezc@salud.madrid.org.|Innate Immunity Group, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.|Center for Biomedical Research Network, Center for Biomedical Research on Respiratory Diseases, 28029 Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood*; D001773:Blood Cells / Q000276:immunology*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000097:blood*; D004731:Endotoxins / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007239:Infections / Q000209:etiology / Q000276:immunology*; D007511:Ischemia / Q000150:complications / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D020521:Stroke / Q000150:complications / Q000276:immunology*
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D004731:Endotoxins