Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.
- Liu Q Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Johnson EM Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Lam RK Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
- Wang Q Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Bo Ye H Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Wilson EN Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Minhas PS Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Liu L Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
- Swarovski MS Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Tran S Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Wang J Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Mehta SS Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Yang X Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Rabinowitz JD Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
- Yang SS Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Shamloo M Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
- Mueller C Institute of Pathology, University of Bern, Bern, Switzerland.
- James ML Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
- Andreasson KI Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. kandreas@stanford.edu.
- 2019-07-03
Published in:
- Nature immunology. - 2019
Animals
Brain
Cell Line
Immunity, Innate
Inflammation
Intestinal Mucosa
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils
RAW 264.7 Cells
Stroke
Triggering Receptor Expressed on Myeloid Cells-1
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1038/s41590-019-0421-2
- PMID 31263278
- Persistent URL
- https://folia.unifr.ch/global/documents/170380
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