Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.
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Liu Q
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Johnson EM
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Lam RK
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
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Wang Q
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Bo Ye H
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Wilson EN
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Minhas PS
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Liu L
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
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Swarovski MS
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Tran S
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Wang J
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Mehta SS
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Yang X
Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Rabinowitz JD
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
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Yang SS
Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Shamloo M
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
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Mueller C
Institute of Pathology, University of Bern, Bern, Switzerland.
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James ML
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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Andreasson KI
Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. kandreas@stanford.edu.
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Published in:
- Nature immunology. - 2019
English
Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.
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Language
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Open access status
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green
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Persistent URL
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https://sonar.ch/global/documents/170380
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