TY  - JOUR
AU  - Rehman, Rida
AU  - Froehlich, Albrecht
AU  - Olde Heuvel, Florian
AU  - Elsayed, Lobna
AU  - Boeckers, Tobias
AU  - Huber-Lang, Markus
AU  - Morganti-Kossmann, Cristina
AU  - Roselli, Francesco
TI  - The FGFR inhibitor Rogaratinib reduces microglia reactivity and synaptic loss in TBI.
JO  - Frontiers in immunology
VL  - 15
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DZNE-2024-01396
SP  - 1443940
PY  - 2024
AB  - Traumatic brain injury (TBI) induces an acute reactive state of microglia, which contribute to secondary injury processes through phagocytic activity and release of cytokines. Several receptor tyrosine kinases (RTK) are activated in microglia upon TBI, and their blockade may reduce the acute inflammation and decrease the secondary loss of neurons; thus, RTKs are potential therapeutic targets. We have previously demonstrated that several members of the Fibroblast Growth Factor Receptor (FGFR) family are transiently phosporylated upon TBI; the availability for drug repurposing of FGFR inhibitors makes worthwhile the elucidation of the role of FGFR in the acute phases of the response to TBI and the effect of FGFR inhibition.A closed, blunt, weight-drop mild TBI protocol was employed. The pan-FGFR inhibitor Rogaratinib was administered to mice 30min after the TBI and daily up to 7 days post injury. Phosphor-RTK Arrays and proteomic antibody arrays were used to determine target engagement and large-scale impact of the FGFR inhibitor. pFGFR1 and pFGFR3 immunostaining were employed for validation. As outcome parameters of the TBI injury immunostainings for NeuN, VGLUT1, VGAT at 7dpi were considered.Inhibition of FGFR during TBI restricted phosphorylation of FGFR1, FGFR3, FGFR4 and ErbB4. Phosphorylation of FGFR1 and FGFR3 during TBI was traced back to Iba1+ microglia. Rogaratinib substantially dowregulated the proteomic signature of the neuroimmunological response to trauma, including the expression of CD40L, CXCR3, CCL4, CCR4, ILR6, MMP3 and OPG. Prolonged Rogaratinib treatment reduced neuronal loss upon TBI and prevented the loss of excitatory (vGLUT+) synapses.The FGFR family is involved in the early induction of reactive microglia in TBI. FGFR inhibition selectively prevented FGFR phosphorylation in the microglia, dampened the overall neuroimmunological response and enhanced the preservation of neuronal and synaptic integrity. Thus, FGFR inhibitors may be relevant targets for drug repurposing aimed at modulating microglial reactivity in TBI.
KW  - Animals
KW  - Microglia: drug effects
KW  - Microglia: metabolism
KW  - Brain Injuries, Traumatic: drug therapy
KW  - Brain Injuries, Traumatic: metabolism
KW  - Brain Injuries, Traumatic: immunology
KW  - Mice
KW  - Male
KW  - Synapses: drug effects
KW  - Synapses: metabolism
KW  - Mice, Inbred C57BL
KW  - Phosphorylation: drug effects
KW  - Disease Models, Animal
KW  - Receptor, Fibroblast Growth Factor, Type 1: antagonists & inhibitors
KW  - Receptor, Fibroblast Growth Factor, Type 1: metabolism
KW  - Protein Kinase Inhibitors: pharmacology
KW  - Protein Kinase Inhibitors: therapeutic use
KW  - proteomics (Other)
KW  - reactive microglia (Other)
KW  - receptor tyrosine kinase (Other)
KW  - synapses (Other)
KW  - traumatic brain injury (Other)
KW  - Receptor, Fibroblast Growth Factor, Type 1 (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39635532
C2  - pmc:PMC11614719
DO  - DOI:10.3389/fimmu.2024.1443940
UR  - https://pub.dzne.de/record/273922
ER  -