Available online 3 December 2023, 108565

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Pexidartinib (PLX3397) is a small molecule receptor tyrosine kinase inhibitor of colony stimulating factor 1 receptor (CSF1R) with moderate selectivity over other members of the platelet derived growth factor receptor family. It is approved for treatment of tenosynovial giant cell tumors (TGCT). CSF1R is highly expressed by microglia, which are macrophages of the central nervous system (CNS) that defend the CNS against injury and pathogens and contribute to synapse development and plasticity. Challenged by pathogens, apoptotic cells, debris, or inflammatory molecules they adopt a responsive state to propagate the inflammation and eventually return to a homeostatic state. The phenotypic switch may fail, and disease-associated microglia contribute to the pathophysiology in neurodegenerative or neuropsychiatric diseases or long-lasting detrimental brain inflammation after brain, spinal cord or nerve injury or ischemia/hemorrhage. Microglia also contribute to the growth permissive tumor microenvironment of glioblastoma (GBM). In rodents, continuous treatment for 1–2 weeks via pexidartinib food pellets leads to a depletion of microglia and subsequent repopulation from the remaining fraction, which is aided by peripheral monocytes that search empty niches for engraftment. The putative therapeutic benefit of such microglia depletion or forced renewal has been assessed in almost any rodent model of CNS disease or injury or GBM with heterogeneous outcomes, but a tendency of partial beneficial effects. So far, microglia monitoring e.g. via positron emission imaging is not standard of care for patients receiving Pexidartinib (e.g. for TGCT), so that the depletion and repopulation efficiency in humans is still largely unknown. Considering the virtuous functions of microglia, continuous depletion is likely no therapeutic option but short-lasting transient partial depletion to stimulate microglia renewal or replace microglia in genetic disease in combination with e.g. stem cell transplantation or as part of a multimodal concept in treatment of glioblastoma appears feasible. The present review provides an overview of the preclinical evidence pro and contra microglia depletion as a therapeutic approach.

Section snippetsList of abbreviations

ADMEAbsorption, distribution, metabolism, and excretionADRAdriamycinAIN-76ARodent dietALSAmyotrophic lateral sclerosisALSPAdult-onset leukoencephalopathy with axonal spheroids and pigmented gliaASDAutism spectrum diseaseATPAdenosine triphosphateAUCArea under the curveBALB/cMouse lineBBBBlood brain barrierBCASBilateral common carotid artery stenosis (stroke model)C57BL/6Mouse lineCAGPromoter construct consisting of the cytomegalovirus (CMV) enhancer fused to the chicken

CSF1R structure and functions

Colony stimulating factor receptor 1 (CSF1R) is a receptor tyrosine kinase belonging to the platelet-derived growth factor receptor (PDGFR) family including PDGF-α and –β, the fms-like tyrosine kinase 3 (FLT3) and the receptor for stem cell factor (c-KIT). CSF1R is expressed in myeloid cells including macrophages, monocytes, microglia and osteoclasts and is tightly regulated at the transcriptional level via a promoter upstream of exon 2 and an fms intronic regulatory element (FIRE) that works

Author contributions

MPW created Table 2&3, JS created Table 1, MKS edited Table 1, discussed and edited the manuscript, IT initiated the project, has written, edited, finalized and revised the manuscript, edited Table 2&3, and created of the figures. All authors contributed to writing or editing parts of the manuscript and agreed to submission of the final version.

Funding

The work was supported by the Deutsche Forschungsgemeinschaft (CRC1080 C02 to IT and TE 322/11-1 to IT). The funding institution had no role in data collection, analysis, preparation of the manuscript or decision to publish.

CRediT authorship contribution statement

Marc-Philipp Weyer: Investigation. Jenny Strehle: Investigation. Michael K.E. Schäfer: Conceptualization, Investigation, Writing – review & editing. Irmgard Tegeder: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

Uncited references

Wang et al., 2021

Wang et al., 2022

Wang et al., 2023

Wang et al., 2022

Declaration of Competing Interest

The authors declare that they have no competing financial interests or other competing interests or personal relationships that could be perceived to have influenced the work reported in this paper.

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