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

Abstract

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

Induction of BVR-A Expression by Korean Red Ginseng in Murine Hippocampal Astrocytes: Role of Bilirubin in Mitochondrial Function via the LKB1–SIRT1–ERRα Axis

“…We next investigated the mechanisms linking bilirubin production and ERRα upregulation in KRGE-treated astrocytes. A recent report demonstrated that LKB1-deficient astrocytes exhibit impaired metabolic function and enhanced inflammatory activation [ 18 ]. Interestingly, bilirubin increased LKB1 phosphorylation in a concentration-dependent manner ( Figure 3 b).…”

“…The energy metabolism kinase LKB1 helps maintain ATP levels and is critical for neuronal survival following mitochondrial dysfunction [ 19 ]. LKB1-deficient astrocytes exhibit impaired metabolic function and enhanced inflammatory activation [ 18 ]. Under physiological circumstances, KRGE activates the LKB1–SIRT1–ERRα pathway, thereby stimulating Tom20/Tom22 complex-mediated SIRT5 expression.…”

Liver Kinase B1 Functions as a Regulator for Neural Development and a Therapeutic Target for Neural Repair

“…It is crucial to determine if LKB1 signaling controls the metabolism and function of oligodendrocytes and OPCs, and if LKB1 deficiency causes mitochondrial dysfunction and progressive axon degeneration of CNS neurons. LKB1 deficiency in astrocytes has been reported to reduce astrocytic metabolic function and enhance inflammatory responses [ 95 ]. The LKB1-AMPK signaling pathway may also modulate the actions of microglia under certain conditions [ 96 ].…”

Mechanisms underlying the beneficial effects of physical exercise on multiple sclerosis: focus on immune cells

“…Despite being neither immune progenitors nor strictly classified as innate immune cells, astrocytes can perceive inflammatory signals and regulate neuroinflammation. Some studies have suggested a possible connection between abnormal gene expression in astrocytes or metabolic abnormalities and increased neuroinflammation (223)(224)(225). Wheeler et al (226) utilized single-cell RNA sequencing combined with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations to examine astrocytes in MS and EAE.…”