Abstract
Immunomodulatory therapies have fueled interest in targeting microglial cells as part of the innate immune response after infection or injury. In this context, the colony-stimulating factor 1 (CSF-1) and its receptor (CSF-1R) have gained attention in various neurological conditions to deplete and reprogram the microglia/macrophages compartment. Published data in physiological conditions support the use of small-molecule inhibitors to study microglia/macrophages dynamics under inflammatory conditions and as a therapeutic strategy in pathologies where those cells support disease progression. However, preclinical and clinical data highlighted that the complexity of the spatiotemporal inflammatory response could limit their efficiency due to compensatory mechanisms, ultimately leading to therapy resistance. We review the current state-of-art in the field of CSF-1R inhibition in glioma and stroke and provide an overview of the fundamentals, ongoing research, potential developments of this promising therapeutic strategy and further application toward molecular imaging.
Highlights
Inflammation is a biological process triggered by injuries, infections and damages suffered by the cells that disrupt tissue homeostasis
We demonstrated that colony stimulating factor-1 receptor (CSF-1R) inhibition transiently decreased neuroinflammation within the infarct, while a sustained decrease was observed in the contralateral healthy tissue, correlating with Iba-1+ dynamics
Seven days of CSF-1R inhibitor (PLX3397) in a non-human primate resulted in a significant reduction of 11C-PBR28 (TSPO) volumes of distribution by 46% from baseline, consistent with microglia depletion, which recovered after 12 days, supporting translocator protein (TSPO)-PET as a CSF-1R inhibition therapy readout [99]
Summary
Inflammation is a biological process triggered by injuries, infections and damages suffered by the cells that disrupt tissue homeostasis. A low level of CSF-1 stimulates microglia survival and inhibits protein degradation, while increased CSF-1 expression, as observed in inflammatory conditions, was associated with cell proliferation and enhanced migration [26]. While CSF-1R inhibition reduces the GAMM density, resistant cell populations were observed across different tumour types, including glioma [65, 66].
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