Macrophage expression of the CSF1R gene is regulated by the promoter upstream of exon 2 and another highly conserved region termed the fms intronic regulatory element (FIRE).

[8] Upon binding of ligand to extracellular Ig domains, CSF1R dimerizes noncovalently and autophosphorylates several tyrosine residues.

This first wave of CSF1R tyrosine phosphorylation creates phosphotyrosine-binding domains to which effector proteins can bind and initiate various cellular responses.

Many proteins become tyrosine phosphorylated in response to CSF1R signaling (Table 1) including p85, Cbl, and Gab3 which are important for survival, differentiation, chemotaxis, and actin cytoskeleton of myeloid cells.

Both ligands regulate myeloid cell survival, proliferation, and differentiation, but CSF-1 and IL-34 differ in their structure, distribution in the body, and the specific cellular signaling cascades triggered upon binding to CSF1R.

[10] Lastly, activation of CSF1R is a strong chemokinetic signal, inducing macrophage polarization and chemotaxis towards the source of CSF1R ligand.

This macrophage response requires rapid morphological changes which is achieved by remodeling of the actin cytoskeleton via the Src/ Pyk2 and PI3K signaling pathways.

CSF1R signaling promotes migration of primitive microglia precursor cells from the embryonic yolk sac to the developing brain prior to formation of the blood-brain-barrier.

[13] Production of CSF1R ligands CSF-1 and IL-34 is increased in the brain following injury or viral infection, which directs microglia to proliferate and execute immune responses.

[8] Studies using early mouse embryos in vitro have shown that activation of CSF1R stimulates formation of the blastocyst cavity and enhances the number of trophoblast cells.

Csf1r loss-of-function mice exhibit several reproductive system abnormalities in the estrous cycle and ovulation rates as well as reduced antral follicles and ovarian macrophages.

[14] In animal models of rheumatoid arthritis, administration of CSF-1 increases the severity of disease whereas Csf1r loss-of-function reduces inflammation and joint erosion.

[15] Tumor-associated macrophages (TAMs) react to early stage cancers with anti-inflammatory immune responses that support tumor survival at the expense of healthy tissue.

Production of CSF-1 by brain tumors called glioblastomas causes microglia (brain-resident macrophages) to exhibit immunosuppressive, tumor-permissive phenotypes.

Heterozygous mutations in the CSF1R gene prevent downstream CSF1R signaling and cause an autosomal dominant neurodegenerative disease called adult-onset leukoencephalopathy, which is characterized by dementia, executive dysfunction, and seizures.

Similarities between Nasu-Hakola disease (caused by mutations in either DAP12 or TREM2) and adult-onset leukoencephalopathy suggest partial loss of microglia CSF1R signaling promotes neurodegeneration.

Defects in neurogenesis and neuronal survival are also seen in adult-onset leukoencephalopathy due to impaired CSF1R signaling in neural progenitor cells.

In Charcot-Marie-Tooth disease type 1, CSF-1 secretion from endoneurial cells stimulates proliferation and activation of macrophages and microglia that cause demyelination.

Several studies have investigated the efficacy of CSF1R inhibitor as a monotherapy and as a combination therapy in refractory and metastatic cancers.

Several small molecule inhibitors and monoclonal antibodies targeting CSF1R are in clinical development for cancer therapy (Table 2).

Several completed and concurrent clinical trials have tested the efficacy and safety of Pexidartinib as a monotherapy for c-kit-mutated melanoma, prostate cancer, glioblastoma, classical Hodgkin lymphoma, neurofibroma, sarcoma, and leukemias.

The safety of CSF1R inhibitors has been extensively characterized in clinical trials for the different small molecules and monoclonal antibodies in Table 2.

[16] CSF1R inhibitors such as PLX5622 are widely used to study the role of microglia in mouse preclinical models of Alzheimer's disease, stroke, traumatic brain injury, and aging.

[13] In 2020, researchers David Hume (University of Queensland) and Kim Green (UCI) published a letter in the academic journal PNAS defending the use small molecule CSF1R inhibitors to study microglia in brain disease.

[26] Colony stimulating factor 1 receptor has been shown to interact with: This article incorporates text from the United States National Library of Medicine, which is in the public domain.