Abstract
Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Therefore, we hypothesized that the molecular profile of microglia may be affected in HDLS. Semi-quantitative immunohistochemistry and quantitative transcriptomic profiling revealed reduced expression of IBA-1 and P2RY12 in both white and gray matter microglia of HDLS. In contrast, there was increased expression of CD68 and CD163 in microglia in affected white matter. In addition, expression of selective and specific microglial markers, including P2RY12, CX3CR1 and CSF-1R, were reduced in affected white matter. These results suggest that microglia in white matter in HDLS lose their homeostatic phenotype. Supported by gene ontology analysis, it is likely that an inflammatory phenotype is a key pathogenic feature of microglia in vulnerable brain regions of HDLS. Our findings suggest a potential mechanism of disease pathogenesis by linking aberrant CSF-1 signaling to altered microglial phenotype. They also support the idea that HDLS may be a primary microgliopathy. We observed increased expression of CSF-2 in gray matter compared to affected white matter, which may contribute to selective vulnerability of white matter in HDLS. Our findings suggest that methods that restore the homeostatic phenotype of microglia might be considered treatment approaches in HDLS.
Highlights
Macrophages are a diverse family of phagocytic effector cells of innate immunity
Alterations in microglial and macrophage phenotypes in hereditary diffuse leukoencephalopathy with spheroids (HDLS) The focus of this study is on a series of patients with CSF1R-related leukoencephalopathy consistent with HDLS [2]
The selectivity of certain regions of cerebral white matter in HDLS is difficult to explain given that CSF1R mutations should affect cells that are dependent upon CSF-1 signaling in both gray and white matter of all brain regions
Summary
Macrophages are a diverse family of phagocytic effector cells of innate immunity. They play vital roles in defense against pathogens as well as clearance of tissue debris and repair of damaged tissue [13]. Limited functional studies of CSF-1 signaling associated with human pathology have been reported [50]. It has been discovered that autosomal dominant mutations in CSF1R, resulting in partial loss of function in CSF-1R signaling, are the major genetic cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS) [22, 40, 44]. There are families with nearly identical antemortem clinical findings confirmed and HDLS-like pathology at autopsy without mutations in either CSF1R or AARS2 [Wszolek, ZK, unpublished]. CSF-1R signaling mediates important cues for survival, proliferation, differentiation and activation of cells of the macrophage lineage, including microglia [17]
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