Met/HGFR triggers detrimental reactive microglia in TBI

Rehman, Rida; Miller, Michael; Krishnamurthy, Sruthi Sankari; Kjell, Jacob; Elsayed, Lobna; Hauck, Stefanie M.; Heuvel, Florian Olde; Conquest, Alison; Chandrasekar, Akila; Ludolph, Albert; Boeckers, Tobias; Mulaw, Medhanie A.; Goetz, Magdalena; Morganti-Kossmann, Maria Cristina; Takeoka, Aya and Roselli, Francesco (2022): Met/HGFR triggers detrimental reactive microglia in TBI. In: Cell Reports, Vol. 41, No. 13, 111867

Abstract

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 dy-namics 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 me-diators, 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 prom-ising translational potential.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2211-1247
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 251293561
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 443642953
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 431995586