The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)

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.

Keywords: colony stimulating factor-1 receptor; glioma; microglia/macrophages; neuroinflammation; positron emission tomography; stroke.

Figure 1

CSF-1R inhibition monotherapy in glioma. In glioma models, CSF-1R inhibition delays recurrence, and therefore slightly prolong overall survival with no significant effect on tumour growth. Reported resistance mechanisms to CSF-1R inhibition include increased insulin-like growth factor (IGF-1) signaling between macrophages and tumor cells, ultimately promoting tumor cell survival and invasion (77), increased levels of granulocyte-macrophage (GM)-CSF and interferon (IFN)- γ, leading to TAM persistence (66) and increased tumor-associated lymphocytes infiltration favoring the immunosuppressive PD-1/PD-L1 signaling (78). Created with Biorender.com.

Figure 2

CSF-1R inhibition monotherapy in stroke. (A) Previous studies on brain pre-conditioning reported the absence of microglial cells within the first days post ischemia (acute phase) worsened disease outcomes, including increased brain injury, peripheral infiltration and pro-inflammatory signaling, ultimately leading to aggravated neurodeficits. (B) Long-term treatment reveals the existence of an Iba-1⁺ (microglia/macrophages) cell population resistant to CSF-1R inhibition while global expression of inflammation-related markers was decreased. Long-term CSF-1R inhibition starting right after surgery led to aggravated motor functions, partly explained by homeostatic imbalance and impaired infarct reperfusion (88). Created with Biorender.com.

Figure 3

Emerging targets for in vivo imaging of CSF-1R inhibition-induced microglial activity modulation. TSPO PET tracers have been widely used to assess neuroinflammation in different pathologies while they have shown some caveats, including inability to distinguish cellular sources of TSPO and phenotypes. Some of the newly investigated targets including P2X7R and P2Y12R highlight the different functions of microglial cells in an inflammatory environment. Created with Biorender.com.