Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy

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.

A Novel Missense Mutation of the CSF1R Gene Causes Incurable CSF1R-Related Leukoencephalopathy: Case Report and Review of Literature

“… 74 Deep cortical layers could be more vulnerable than superficial cortical layers in patients with CSF1R -related leukoencephalopathy. 75 …”

“…74 Deep cortical layers could be more vulnerable than superficial cortical layers in patients with CSF1R-related leukoencephalopathy. 75 CSF1R-related leukoencephalopathy is a rare but rapidly progressive neurodegenerative disease. A clinical diagnosis of CSF1R-related leukoencephalopathy should be considered International Journal of General Medicine 2020:13 submit your manuscript | www.dovepress.com…”

Attenuated CSF‐1R signalling drives cerebrovascular pathology

“…Upregulation of Mif expression has been implicated in the activation of microglial‐mediated inflammatory processes and has recently been proposed to be a biomarker of Alzheimer’s disease (Zhang et al , 2016, 2019). Furthermore, MIF expression has been demonstrated to enhance tight junction breakdown and blood–brain barrier permeability in stroke (Liu et al , 2018), and MIF‐mediated processes are reported to be significantly altered in ALSP frontal cortex white matter (Kempthorne et al , 2020). The restriction of these transcriptional changes in TJ components , Il34 and Mif to Csf‐1r +/− endothelial cells responding to soluble factors from Csf‐1r +/− microglia indicates CSF‐1R as a key regulator of microglial‐endothelial crosstalk.…”

Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

“…Microglia are adapted to the CNS microenvironment and express specific gene signatures ( P2ry12 , Tmem119 and SiglecH ) in order to perform tissue-specific functions [ 39 ]. In CSF1R -related leukoencephalopathy, loss of Iba1 + /P2ry12 + microglia were observed in vulnerable cerebral white matter, but not in unaffected grey matter [ 40 ]. Microglia exhibit a distinct morphology with narrow cytoplasm and fragmented processes containing beaded structures, differing from activated microglia that are characterized with retracted processes and enlarged cytoplasm in e.g.…”

“…We have previously reported that long-term microglial depletion leads to monocyte colonization of the empty niche [ 44 ]. The functional role of infiltrating monocyte-derived cells in CSF1R -related leukoencephalopathy remains to be investigated [ 40 ].…”