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Rehman, R.* ; Miller, M.* ; Krishnamurthy, S.S.* ; Kjell, J. ; Elsayed, L.* ; Hauck, S.M. ; olde Heuvel, F.* ; Conquest, A.* ; Chandrasekar, A.* ; Ludolph, A.* ; Boeckers, T.* ; Mulaw, M.A.* ; Götz, M. ; Morganti-Kossmann, M.C.* ; Takeoka, A.* ; Roselli, F.*

Met/HGFR triggers detrimental reactive microglia in TBI.

Cell Rep. 41:111867 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The complexity of signaling events and cellular responses unfolding in neuronal, glial, and immune cells upon traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We use array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then scrutinize the large-scale effects of perturbation of Met/HGFR, VEGFR1, and Btk signaling by small molecules. We show Met/HGFR as a selective modifier of early microglial response and that Met/HGFR blockade prevents the induction of microglial inflammatory mediators, of reactive microglia morphology, and TBI-associated responses in neurons and vasculature. Both acute and prolonged Met/HGFR inhibition ameliorate neuronal survival and motor recovery. Early elevation of HGF itself in the cerebrospinal fluid of TBI patients suggests that this mechanism has translational value in human subjects. Our findings identify Met/HGFR as a modulator of early neuroinflammation in TBI with promising translational potential.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Antibody Array ; Btk ; Cp: Neuroscience ; Hgfr ; Met ; Microglia ; Neuroinflammation ; Phosphorylation ; Proteomics ; Traumatic Brain Injury ; Vegfr; Hepatocyte Growth-factor; Traumatic Brain-injury; Tyrosine Kinase Inhibitor; C-met; Neuron Degeneration; Cytokine Production; Receptors Triggers; Tumor-growth; Cell-types; Activation
Language english
Publication Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 41, Issue: 13, Pages: , Article Number: 111867 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
CF Metabolomics & Proteomics (CF-MPC)
POF-Topic(s) 30204 - Cell Programming and Repair
30203 - Molecular Targets and Therapies
Research field(s) Stem Cell and Neuroscience
Enabling and Novel Technologies
PSP Element(s) G-500800-001
G-505700-001
A-630700-001
Grants Fonds Wetenschappelijk Onderzoek
Bundesministerium für Bildung und Forschung
Deutsche Forschungsgemeinschaft
Hannelore Kohl Foundation
DOI 10.1016/j.celrep.2022.111867
WOS ID 000916492600001
WOS ID WOS:000916492600001
Scopus ID 85144885515
PubMed ID 36577378
Erfassungsdatum 2023-01-10
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