TY - JOUR
T1 - Met/HGFR triggers detrimental reactive microglia in TBI
AU - Rehman, Rida
AU - Miller, Michael
AU - Krishnamurthy, Sruthi Sankari
AU - Kjell, Jacob
AU - Elsayed, Lobna
AU - Hauck, Stefanie M
AU - Olde Heuvel, Florian
AU - Conquest, Alison
AU - Chandrasekar, Akila
AU - Ludolph, Albert
AU - Boeckers, Tobias
AU - Mulaw, Medhanie A
AU - Goetz, Magdalena
AU - Morganti-Kossmann, Maria Cristina
AU - Takeoka, Aya
AU - Roselli, Francesco
N1 - Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2022.111867
DO - 10.1016/j.celrep.2022.111867
M3 - Journal articles
C2 - 36577378
SN - 2211-1247
VL - 41
SP - 111867
JO - Cell Rep
JF - Cell Rep
IS - 13
ER -