Article
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
Search Medline for
Authors
Published: | May 25, 2022 |
---|
Outline
Text
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.