CSF1R Microglia: Vital Drivers of Neuroinflammatory Pathways

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining brain health. Their function is tightly regulated by colony-stimulating factor 1 receptor (CSF1R), which controls their survival, proliferation, and activation. CSF1R signaling dictates how these cells respond to injury, infection, and neurodegenerative conditions, making it a key player in neuroinflammation. Understanding its role provides insight into disease mechanisms and potential therapeutic targets for neurological disorders.

Receptor Location And Expression

CSF1R is predominantly expressed on microglia within the CNS, serving as a defining marker for these cells. Unlike peripheral macrophages, which also express CSF1R, microglia exhibit a more tightly regulated expression pattern. The CSF1R gene, located on chromosome 5q32, is influenced by developmental and environmental cues. During embryogenesis, microglial progenitors from the yolk sac migrate into the brain, where CSF1R expression becomes essential for their differentiation and maintenance. Studies using CSF1R-deficient mice have shown that its absence leads to a near-complete loss of microglia, underscoring its critical role.

Within the CNS, CSF1R is primarily localized to microglial membranes, where it interacts with its ligands, colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34). These ligands exhibit distinct spatial expression patterns, with CSF1 being more abundant in white matter and IL-34 in the cortex and hippocampus. This distribution suggests that CSF1R signaling is regionally modulated, allowing microglia to adapt their functions based on local demands. Advanced imaging techniques such as single-cell RNA sequencing and immunohistochemistry have revealed fluctuations in CSF1R expression across developmental stages, aging, and pathological conditions.

Beyond microglia, CSF1R is also expressed in CNS-associated macrophages, including perivascular, meningeal, and choroid plexus macrophages. These populations share functional similarities with microglia but have distinct transcriptional profiles and localization patterns. While neurons and astrocytes do not typically express CSF1R, some studies suggest its upregulation in pathological states, raising questions about its potential involvement in non-microglial CNS processes.

Role In Cell Signaling

CSF1R signaling regulates microglial survival, proliferation, and differentiation through a cascade of intracellular events. Upon ligand binding, CSF1R undergoes autophosphorylation at key tyrosine residues, triggering downstream pathways such as phosphoinositide 3-kinase (PI3K)/Akt for cell survival and mitogen-activated protein kinase (MAPK) for proliferation and differentiation. Disruptions in CSF1R signaling, whether from genetic mutations or pharmacological inhibition, can profoundly alter microglial homeostasis.

The availability of CSF1R’s two primary ligands, CSF1 and IL-34, further refines its signaling. IL-34 has a higher affinity for CSF1R and sustains receptor activation for longer periods, while CSF1 is more transiently expressed, driving dynamic changes in microglial proliferation. This ligand-specific modulation allows microglia to adapt their responses to regional and temporal variations in signaling cues.

CSF1R signaling is also subject to regulatory mechanisms that prevent excessive microglial expansion. Negative regulators such as suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases (PTPs) attenuate signaling intensity. Additionally, receptor internalization and degradation via ubiquitination pathways ensure balanced signaling. Dysregulation of these control mechanisms has been implicated in neurodevelopmental and neurodegenerative disorders, highlighting the importance of maintaining proper CSF1R activity.

Influence On Microglial Functions

CSF1R signaling maintains microglial population dynamics, ensuring stable presence within the CNS. Unlike peripheral macrophages, which can be replenished from bone marrow-derived progenitors, microglia are largely self-sustaining, with their proliferation tightly controlled by CSF1R activity. Pharmacological inhibition of CSF1R leads to rapid microglial depletion, followed by repopulation once inhibition is lifted, demonstrating its role in both maintenance and regeneration.

Beyond population control, CSF1R influences microglial morphology and interactions with neural structures. Microglia continuously extend and retract their processes to survey their environment, a behavior regulated by CSF1R signaling. Reduced receptor activity leads to retracted, less motile microglial processes, affecting synaptic interactions. In synaptic pruning, microglia deficient in CSF1R signaling exhibit impaired synapse elimination, underscoring the receptor’s role in refining neural circuits.

CSF1R signaling also dictates microglial metabolism, influencing energy utilization and functional capacity. Microglia shift between oxidative phosphorylation and glycolysis depending on their activity demands. CSF1R activation enhances mitochondrial function, supporting microglial endurance in high-energy-demand states. Disruptions in CSF1R signaling contribute to metabolic deficits, impairing microglial efficiency, particularly in aging and neurodegenerative conditions.

Link To Neuroinflammatory Processes

CSF1R signaling shapes neuroinflammatory dynamics by regulating microglial responses. Under normal conditions, CSF1R maintains microglia in a surveillance state, allowing them to monitor the brain environment. When pathological stimuli arise, such as protein aggregates or tissue damage, CSF1R signaling shifts microglia toward a reactive phenotype, altering gene expression, cytoskeletal structure, and inflammatory molecule release. The extent and duration of this response are tightly linked to CSF1R activity, with excessive signaling amplifying neuroinflammation and insufficient signaling impairing appropriate microglial function.

In chronic neurological disorders, CSF1R’s role in neuroinflammation is particularly evident. In Alzheimer’s disease, upregulated CSF1R expression in microglia surrounding amyloid plaques suggests an attempt to clear pathological aggregates. However, prolonged activation can sustain inflammatory signaling, leading to neuronal stress and synaptic dysfunction. Similarly, in Parkinson’s disease, increased CSF1R-mediated microglial proliferation in the substantia nigra correlates with dopaminergic neuron loss. These findings highlight the dual nature of CSF1R-driven neuroinflammation—while initially protective, persistent activation can exacerbate disease progression.

Interplay With Other CNS Cells

CSF1R-mediated microglial activity is intricately connected to other CNS cells, influencing brain homeostasis, plasticity, and disease progression. Neurons, astrocytes, and oligodendrocytes interact with microglia in ways that shape both physiological and pathological processes.

Neurons modulate microglial behavior through CSF1R ligands such as IL-34, affecting synaptic remodeling. Neuronal activity patterns influence microglial positioning, with hyperactive or stressed neurons triggering microglial responses that can be protective or detrimental. In neurodegenerative diseases, dying neurons enhance CSF1R activation, increasing microglial presence in affected regions. While this initially aids in debris clearance, sustained activation can lead to chronic neuroinflammation. Evidence from neurodevelopmental disorders such as schizophrenia suggests that dysregulated CSF1R signaling may contribute to synaptic deficits by altering microglial pruning activity.

Astrocytes modulate CSF1R-dependent microglial functions by releasing cytokines and growth factors. Under normal conditions, they secrete anti-inflammatory mediators that limit excessive activation. In pathological states, reactive astrocytes enhance CSF1R signaling, driving microglial proliferation and inflammation. This is particularly evident in multiple sclerosis, where astrocyte-derived factors recruit microglia to demyelinated lesions.

Oligodendrocytes, responsible for myelination, are also influenced by CSF1R-mediated microglial activity, particularly in injury and repair processes. Microglia facilitate oligodendrocyte precursor cell maturation by clearing myelin debris, a function impaired when CSF1R signaling is disrupted. This impairment has been linked to delayed remyelination in multiple sclerosis, illustrating CSF1R’s broad impact on CNS cellular interactions.