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Met/HGFR triggers detrimental reactive microglia in TBI.

Abstract (Expand)

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.

Authors: Rida Rehman, Michael Miller, Sruthi Sankari Krishnamurthy, Jacob Kjell, Lobna Elsayed, Stefanie M Hauck, Florian Olde Heuvel, Alison Conquest, Akila Chandrasekar, Albert Ludolph, Tobias Boeckers, Medhanie A Mulaw, Maria Cristina Morganti-Kossmann, Aya Takeoka, Francesco Roselli, Magdalena Götz

Date Published: 27th Dec 2022

Publication Type: Journal

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