gms | German Medical Science

73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

Large-scale architecture of tyrosine kinase signaling in neurotrauma reveals HGF/Met as early inducers of reactive microglia

Groß angelegte Architektur der Tyrosinkinase-Signalübertragung bei Neurotrauma zeigt HGF/Met als frühen Auslöser reaktiver Mikroglia

Meeting Abstract

  • Rida Rehman - Universitätsklinikum Ulm, Neurology, Ulm, Deutschland
  • Akila Chandrasekar - Universitätsklinikum Ulm, Neurology, Ulm, Deutschland
  • Florian olde Heuvel - Universitätsklinikum Ulm, Neurology, Ulm, Deutschland
  • Shun Li - Universitätsklinikum Ulm, Neurology, Ulm, Deutschland
  • Maria Cristina Morganti-Kossmann - The Alfred Hospital, Melbourne, Australien
  • presenting/speaker Francesco Roselli - Universitätsklinikum Ulm, Neurology, Ulm, Deutschland; German Center for Neurodegenerative Diseases, Ulm, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP198

doi: 10.3205/22dgnc512, urn:nbn:de:0183-22dgnc5128

Published: May 25, 2022

© 2022 Rehman et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at



Objective: The signaling events cellular responses unfolding in neuronal, glial and immune cells upon Traumatic brain injury (TBI) are highly complex. Their characterization may reveal a number of new targets for intervention.

Methods: We used array phosphoproteomics and quantitative immunohistology in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI. We used pharmacology and quantitative motor assessment to determine the effectiveness of small-molecule interventions on the new targets identified.

Results: We identified several receptor-tyrosine kinase (RTK) families with distinct temporal dynamics and characteristic up or down-regulation (Figure 1 [Fig. 1]). The RTK phosphorylation landscape was significantly affected by the intensity of the trauma. We used phosphoproteomic arrays to expand the characterization of tyrosine kinase signaling, including a number of downstream cascades and revealing substantial phosphorylation of Btk and Fer. We scrutinized the large-scale effects of the small-molecule perturbation of cMet/HGFR, VEGFR1 and Btk signaling. cMet/HGFR was a modifier of the early microglial response, and cMet/HGFR blockade prevented the induction of inflammatory mediators, of reactive microglia morphology and of TBI-associated neuronal and vascular stress. 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.

Conclusion: 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, paving the way to drug-repurposing investigations.