Met/HGFR triggers detrimental reactive microglia in TBI
Met/HGFR triggers detrimental reactive microglia in TBI
Abstract The complexity of the signaling events, 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 used array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then to scrutinize the large-scale effects of the perturbation of cMet/HGFR, VEGFR1 and Btk signaling by small molecules. cMet/HGFR emerged as a selective modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of microglial inflammatory mediators, of reactive microglia morphology and of TBI-associated responses in neurons, vessels and brain extracellular matrix. Acute or prolonged cMet/HGFR inhibition ameliorated neuronal survival and motor recovery. Early elevation of HGF itself in the CSF of TBI patients suggest that this mechanism has translational value in human subjects. Our findings identify cMet/HGFR as a modulator of early neuroinflammation in TBI with translational potential and indicate several RTK families as possible additional targets for TBI treatment. SummaryControlling neuroinflammation in neurotrauma is an important but unachieved goal. This study exploits a moderate TBI model and array-based proteomics to identify cMet as a new inducer of reactive microglia. A small-molecule inhibitor of cMet contains microglial reactivity, reduces neuronal and vascular alterations, limits behavioural disturbances and accelerates recovery. HighlightsMet is activated in microglia upon TBI and drives microglial reactivity.A Met inhibitor reduces motor dysfunction upon TBI and promotes recovery.Blockade of MET prevents the appearance of a reactive microglia.The cMET inhibitor reduces the sub-acute neuronal loss after TBI.
Kjell Jacob、olde Heuvel Florian、Conquest Alison、Mulaw Medhanie A、Morganti-Kossmann Maria Cristina、Takeoka Aya、Miller Michael、Rehman Rida、Boeckers Tobias、Elsayed Lobna、Krishnamurthy Sruthi Sankari、Goetz Magdalena、Roselli Francesco、Ludolph Albert、Chandrasekar Akila
Institute for Stem Cell Research, Helmholtz Zentrum M¨1nchen & Biomedical Center, Ludwig-Maximilians Universitaet||Department of Clinical Neuroscience, Karolinska InstitutetDept. of Neurology, Ulm UniversityNational Trauma Research Institute and Department of Neurosurgery, The Alfred HospitalDept. of Internal Medicine I and Institute of Molecular Medicine, Ulm UniversityNational Trauma Research Institute and Department of Neurosurgery, The Alfred Hospital||Department of Epidemiology and Preventive Medicine, Monash UniversityNeuro-Electronics Research Flanders (NERF), Flanders Institute for Biotechnology (VIB)||Department of Neuroscience and Leuven Brain Institute||IMECNeuro-Electronics Research Flanders (NERF), Flanders Institute for Biotechnology (VIB)||Department of Neuroscience and Leuven Brain InstituteDept. of Neurology, Ulm UniversityGerman center for Neurodegenerative Diseases (DZNE)-Ulm||Dept. of Internal Medicine I and Institute of Molecular Medicine, Ulm UniversityDept. of Neurology, Ulm UniversityDept. of Neurology, Ulm UniversityInstitute for Stem Cell Research, Helmholtz Zentrum M¨1nchen & Biomedical Center, Ludwig-Maximilians UniversitaetDept. of Neurology, Ulm University||German center for Neurodegenerative Diseases (DZNE)-UlmDept. of Neurology, Ulm University||German center for Neurodegenerative Diseases (DZNE)-UlmDept. of Neurology, Ulm University||Dept. of Cellular Neurobiology, Technical University
神经病学、精神病学基础医学医学研究方法
Traumatic Brain Injuryantibody arrayproteomicscMetHGFRBtkVEGFRmicroglianeuroinflammation
Kjell Jacob,olde Heuvel Florian,Conquest Alison,Mulaw Medhanie A,Morganti-Kossmann Maria Cristina,Takeoka Aya,Miller Michael,Rehman Rida,Boeckers Tobias,Elsayed Lobna,Krishnamurthy Sruthi Sankari,Goetz Magdalena,Roselli Francesco,Ludolph Albert,Chandrasekar Akila.Met/HGFR triggers detrimental reactive microglia in TBI[EB/OL].(2025-03-28)[2025-05-13].https://www.biorxiv.org/content/10.1101/2021.12.05.471232.点此复制
评论