Abstract
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.
Highlights
Microglia are resident innate immune cells in the brain that play crucial roles in the development and homeostasis of the central nervous system (CNS)
A study has found that human interleukin 34 (IL34) drives hematopoietic stem progenitor cell (HSPC)-derived peripheral macrophages into microglial-like cells (Mathews et al, 2019). These results indicate that signaling mediated by colony-stimulating factor 1 receptor (CSF1R) and its ligands colony stimulating factor 1 (CSF1)/IL34 is critical for microglia development and maintenance
CSF1R is necessary for microglia viability (Elmore et al, 2014) whereas Triggering Receptor Expressed on Myeloid cells 2 (TREM2) synergizes with CSF1R signaling to sustain microglial survival (Wang et al, 2015). These results suggest a functional trio of CSF1R, TREM2 and DAP12, in which CSF1R plays a crucial role in microglial population dynamics whereas TREM2 and DAP12 are synergistic to the effect (Figure 1)
Summary
Microglia are resident innate immune cells in the brain that play crucial roles in the development and homeostasis of the central nervous system (CNS). These results indicate that signaling mediated by CSF1R and its ligands CSF1/IL34 is critical for microglia development and maintenance. Given that these molecules are expressed in microglia and mutations in either TREM2, DAP12 or CSF1R are associated with neurodegenerative disorders (Klunemann et al, 2005; Rademakers et al, 2011; Chitu et al, 2021), “microgliopathy” is proposed as a new term to designate conditions where microglial dysfunction is the primary and at the center of the disease process (Sasaki, 2017; Zheng et al, 2018).
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