Abstract
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease characterized by inflammatory demyelination, and activated astrocytes as well as microglia are thought to be involved in its pathogenesis. Conditionally immortalized astrocytic cell clones were prepared from wild-type or Abcd1-deficient H-2KbtsA58 transgenic mice to study the involvement of astrocytes in the pathogenesis of X-ALD. The established astrocyte clones expressed astrocyte-specific molecules such as Vimentin, S100β, Aldh1L1 and Glast. The conditionally immortalized astrocytes proliferated vigorously and exhibited a compact cell body under a permissive condition at 33 °C in the presence of IFN-γ, whereas they became quiescent and exhibited substantial cell enlargement under a non-permissive condition at 37 °C in the absence of IFN-γ. An Abcd1-deficient astrocyte clone exhibited a decrease in the β-oxidation of very long chain fatty acid (VLCFA) and an increase in cellular levels of VLCFA, typical features of Abcd1-deficiency. Upon stimulation with LPS, the Abcd1-deficient astrocyte clone expressed higher levels of pro-inflammatory genes, such as Il6, Nos2, Ccl2 and Cxcl10, compared to wild-type (WT) astrocytes. Furthermore, the Abcd1-deficient astrocytes produced higher amounts of chondroitin sulfate, a marker of reactive astrocytes. These results suggest that dysfunction of Abcd1 renders astrocytes highly responsive to innate immune stimuli. Conditionally immortalized cell clones which preserve astrocyte properties are a useful tool for analyzing the cellular and molecular pathology of ALD.
Highlights
Astrocytes are the most abundant glial cells in the central nervous system (CNS) and play important roles in maintaining normal brain homeostasis (Pfrieger and Ungerer 2011; Prat et al, 2001; Kiray et al, 2016)
X-linked adrenoleukodystrophy (X-ALD) is an inherited metabolic disease that induces cerebral inflammatory demyelination (Moser et al, 2007; Kemp et al, 2012). It is caused by mutations in the ABCD1 gene that encodes the peroxisomal ATP-binding cassette transporter ABCD1, which is involved in the transport of very long-chain fatty acids (VLCFA)-CoA into the peroxisome for β-oxidation (Morita and Imanaka 2012)
The SV40LTantigen in these cell lines decreased in a time-dependent manner under the non-permissive condition with growth cessation, indicating that the temperature-sensitive growth characteristic is due to the activity of the SV40LT-antigen
Summary
Astrocytes are the most abundant glial cells in the central nervous system (CNS) and play important roles in maintaining normal brain homeostasis (Pfrieger and Ungerer 2011; Prat et al, 2001; Kiray et al, 2016). X-ALD is an inherited metabolic disease that induces cerebral inflammatory demyelination (Moser et al, 2007; Kemp et al, 2012). It is caused by mutations in the ABCD1 gene that encodes the peroxisomal ATP-binding cassette transporter ABCD1, which is involved in the transport of very long-chain fatty acids (VLCFA)-CoA into the peroxisome for β-oxidation (Morita and Imanaka 2012). It has been speculated that astrocytes and microglia with dysfunctional ABCD1 could play a role as initiators of inflammatory demyelination. Gortz et al (2018) have suggested that certain pathogenic factors that trigger cellular stress in astrocytes may be involved in the activation of microglia and initiation of inflammatory demyelination in X-ALD. The specific contribution of astrocytes to the pathogenesis of X-ALD is still largely undetermined
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