Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis.

摘要: Liver kinase B1 (LKB1) is a ubiquitously expressed involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that single nucleotide polymorphism gene encoding LKB1 risk factor for multiple sclerosis (MS). Since astrocyte activation metabolic function have important roles regulating neuroinflammation neuropathology, we examined serine/threonine astrocytes chronic experimental autoimmune encephalomyelitis mouse model MS. To reduce LKB1, heterozygous astrocyte-selective conditional knockout (het-cKO) was used. While disease incidence similar, severity worsened het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia Genes Genomes (KEGG) pathways enriched mice relating to mitochondrial function, confirmed by alterations complex proteins reductions mRNAs related metabolism. Enriched included major histocompatibility class II genes, increases MHCII protein spinal cord cerebellum observed increased numbers CD4+ Th17 cells neuronal damage cords mice, associated with reduced expression choline acetyltransferase, accumulation immunoglobulin-γ, factors motor neuron survival. In vitro, LKB1-deficient showed These data suggest dysfunction astrocytes, this case due deficiency, can exacerbate demyelinating loss support increase environment.