Soluble CSF1R alleviates microgliopathy in a CSF1R-related leukoencephalopathy (CRL) mouse model.

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03648-4.