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The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant leukodystrophy primarily caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene, characterized by progressive cognitive and motor decline. We present a case of a 42-year-old Chinese woman with a rapidly progressive syndrome featuring prominent apathy, cognitive impairment, and hypoactivity. Brain magnetic resonance imaging (MRI) revealed extensive confluent white matter hyperintensities (Fazekas grade 3) predominantly in frontal and parietal lobes, cerebral atrophy, and thinning of the corpus callosum. Comprehensive genetic testing identified a heterozygous missense mutation in the CSF1R gene (c.2342C > T, p.Ala781Val), located within the tyrosine kinase domain, confirming the Diagnosis of HDLS. This case highlights early apathy and hypoactivity as red-flag manifestations of CSF1R-related leukoencephalopathy in a 42-year-old woman with rapidly progressive cognitive decline. The atypical presentation, initially mimicking psychiatric or demyelinating disease, underscores the need to consider CSF1R sequencing when encountering early-onset cognitive or behavioral deterioration with unexplained white-matter changes, thereby facilitating timely diagnosis and genetic counseling.

Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1β, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.

Colony-stimulating factor 1 receptor (CSF1R), primarily expressed on microglia in the central nervous system (CNS), is essential for microglial homeostasis and survival. CSF1R dysfunction, due to a monoallelic mutation, causes CSF1R-related leukoencephalopathy (CRL), a primary microgliopathy. CSF1R undergoes proteolytic cleavage to release soluble CSF1R (sCSF1R), which is decreased in the serum of CRL patients. However, the biological function of sCSF1R remains unknown. Here, we found that sCSF1R alleviated cognitive impairment and anxiety-like behavior in Csf1r +/− mice. Importantly, we identified CSF1R as a target binding protein of sCSF1R on microglia. Notably, sCSF1R inhibited the activation and inflammatory factor expression of Csf1r +/− microglia by reducing the phosphorylation of CSF1R (Y723) and NF-κB (S468 and S536). These results demonstrate that sCSF1R exerts neuroprotective effects by binding membrane-bound CSF1R and inhibiting pathological microglial activation by inhibiting the nuclear translocation of NF-κB. These findings identify sCSF1R as a potential therapeutic agent for CRL.

Microglia are specialized brain macrophages that play numerous roles in tissue homeostasis and response to injury. Colony stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase required for the development, maintenance, and proliferation of microglia. Here we show that in adult mice peripheral dosing of function-blocking antibodies to the two known ligands of CSF1R, CSF1, and IL-34, can deplete microglia differentially in white and gray matter regions of the brain, respectively. The regional patterns of depletion correspond to the differential expression of CSF1 and IL-34. In addition, we show that while CSF1 is required to establish microglia in the developing embryo, both CSF1 and IL-34 are required beginning in early postnatal development. These results not only clarify the roles of CSF1 and IL-34 in microglia maintenance, but also suggest that signaling through these two ligands might support distinct sub-populations of microglia, an insight that may impact drug development for neurodegenerative and other diseases.

While neuroinflammation is an evolving concept and the cells involved and their functions are being defined, microglia are understood to be a key cellular mediator of brain injury and repair. The ability to measure microglial activity specifically and non-invasively would be a boon to the study of neuroinflammation, which is involved in a wide variety of neuropsychiatric disorders including traumatic brain injury, demyelinating disease, Alzheimer’s disease (AD), and Parkinson’s disease, among others. We have developed [11C]CPPC [5-cyano-N-(4-(4-[11C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide], a positron-emitting, high-affinity ligand that is specific for the macrophage colony-stimulating factor 1 receptor (CSF1R), the expression of which is essentially restricted to microglia within brain. [11C]CPPC demonstrates high and specific brain uptake in a murine and nonhuman primate lipopolysaccharide model of neuroinflammation. It also shows specific and elevated uptake in a murine model of AD, experimental allergic encephalomyelitis murine model of demyelination and in postmortem brain tissue of patients with AD. Radiation dosimetry in mice indicated [11C]CPPC to be safe for future human studies. [11C]CPPC can be synthesized in sufficient radiochemical yield, purity, and specific radioactivity and possesses binding specificity in relevant models that indicate potential for human PET imaging of CSF1R and the microglial component of neuroinflammation.

The CSF1R gene, located on chromosome 5, encodes a 108 kDa protein and plays a critical role in regulating myeloid cell function. Mutations in CSF1R have been identified as a cause of a rare white matter disease called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP, also known as CSF1R-related leukoencephalopathy), characterized by progressive neurological dysfunction. This study aimed to broaden the genetic basis of ALSP by identifying novel CSF1R variants in patients with characteristic clinical and imaging features of ALSP. Genetic analysis was performed through whole-exome sequencing or panel analysis for leukodystrophy genes. Variant annotation and classification were conducted using computational tools, and the identified variants were categorized following the recommendations of the American College of Medical Genetics and Genomics (ACMG). To assess the evolutionary conservation of the novel variants within the CSF1R protein, amino acid sequences were compared across different species. The study identified six previously unreported CSF1R variants (c.2384G>T, c.2133_2919del, c.1837G>A, c.2304C>A, c.2517G>T, c.2642C>T) in seven patients with ALSP, contributing to the expanding knowledge of the genetic diversity underlying this rare disease. The analysis revealed considerable genetic and clinical heterogeneity among these patients. The findings emphasize the need for a comprehensive understanding of the genetic basis of rare diseases like ALSP and underscored the importance of genetic testing, even in cases with no family history of the disease. The study’s contribution to the growing spectrum of ALSP genetics and phenotypes enhances our knowledge of this condition, which can be crucial for both diagnosis and potential future treatments.

Colony‐stimulating factor 1 receptor (CSF1R) is highly expressed in mononuclear phagocytes and in the central nervous system. It has emerged as a promising target for tumor therapy and neuroinflammation imaging. Although therapeutic agents targeting CSF1R have shown great success, the development of diagnostic radiotracers for CSF1R has faced numerous challenges. Consequently, there is an urgent need to overcome these obstacles for the development of CSF1R radiotracers, particularly positron emission tomography tracers, not only for diagnostic purposes but also to aid the development of more effective therapeutic drugs. Here, we provide a comprehensive overview of the development of CSF1R radiotracers, presenting detailed profiles of each tracer's ability to image CSF1R. Additionally, we discuss reported CSF1R small‐molecule inhibitors and antibodies, highlighting their relevance to the further development of CSF1R radiotracers. We aim to shed light on the current state of CSF1R radiotracer research and development, provide an insight into the challenges in this field, and offer guidance for future exploration. In this review, we provide a comprehensive overview of the rapid evolution of colony‐stimulating factor 1 receptor (CSF1R) radiotracers derived from CSF1R‐targeting therapeutic agents. We systematically examine and describe preclinical CSF1R imaging studies conducted in the context of cancers, neurological disorders, and inflammatory disorders. Additionally, the review catalogs reported CSF1R ligands, encompassing small molecules and antibodies, thereby expanding the repertoire of parent molecules for the development of novel CSF1R radiotracers.

Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45 microglia and CD45 myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function.

Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified . By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.