Inhibition of FAK in Astrocytes Alleviates MS Lesions Through LIF and OSM
Abstract
Multiple sclerosis is a chronic inflammatory disease of the central nervous system that leads to demyelination and axonal injury. Protecting myelin and axons and promoting remyelination remain crucial therapeutic challenges in multiple sclerosis. Several extracellular matrix molecules accumulate in the lesion of multiple sclerosis and exacerbate inflammatory responses and inhibit remyelination. Blocking extracellular matrix molecules might be difficult due to their abundance and diversity. Pharmacological inhibition of downstream signaling might be better. Focal adhesion kinase is a non-receptor tyrosine kinase and activated by extracellular matrix molecules. Thus, inhibition of focal adhesion kinase may alleviate multiple sclerosis. In a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), our preliminary data show that focal adhesion kinase in the central nervous system is activated by EAE. Further, systemic treatment with a focal adhesion kinase inhibitor, FAK14, alleviates EAE symptoms, demyelination, and axonal injury. FAK14 treatment did not influence EAE induction or reduce EAE-induced inflammation in the central nervous system. Thus, focal adhesion kinase is a potential target for therapeutic intervention in multiple sclerosis. Astrocytes are the predominant glial (non-neuronal) cells in the central nervous system and play critical roles in myelin maintenance and repair. Identifying factors or pathways in astrocytes that regulate multiple sclerosis pathogenesis may provide new therapeutic targets. Our data indicate that selective and inducible knockout of focal adhesion kinase in astrocytes reduces EAE symptoms and demyelination. Importantly, systemic treatment with FAK14 reduces EAE symptoms in wildtype but not mice lacking focal adhesion kinase in astrocytes, indicating that activation of focal adhesion kinase in astrocytes exacerbates EAE lesions and that FAK14 acts by inhibiting focal adhesion kinase in astrocytes. However, we do not know whether this is caused by reduced demyelination, increased remyelination or changes in cytokine expression. The objective of this proposal is to define the unknown mechanism underlying the beneficial effects of focal adhesion kinase inhibition on EAE and whether this is mainly through astrocytes. Rationale: Our preliminary data suggest that EAE activates focal adhesion kinase, which promotes demyelination and axonal injury, possibly via astrocytes. Leukemia inhibitory factor and oncostatin-M protect myelin and axons in EAE models, and astrocytes express both cytokines. Our data demonstrate that systemic FAK14 treatment following EAE enhances the expression of both cytokines in the central nervous system while not affecting them in the peripheral system. We hypothesize that inhibition of focal adhesion kinase in astrocytes alleviates EAE lesions by upregulating leukemia inhibitory factor and oncostatin-M, which reduces demyelination and axonal injury. We will test this hypothesis with two aims using genetic and pharmacological approaches in a mouse EAE model. Aim 1 will determine whether leukemia inhibitory factor and/or oncostatin-M contribute to the therapeutic effects of focal adhesion kinase inhibition on EAE. Aim 1a will test the effect of neutralization of leukemia inhibitory factor or oncostatin-M in the central nervous system on the role of FAK14 in EAE. Aim 1b will identify whether FAK14 upregulates leukemia inhibitory factor and/or oncostatin-M in astrocytes under EAE conditions. Aim 1c will test how long FAK14-induced leukemia inhibitory factor and oncostatin-M need to be maintained for a long-lasting therapeutic effect, thus exploring translational promise. Aim 2 will determine whether FAK14 reduces demyelination and axon loss in early and chronic phases of EAE through astrocytes using mice lacking focal adhesion kinase in astrocytes. This grant application will focus on the fiscal year 2022 Multiple S
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310895
Entities
People
- Cuihong Jia
Organizations
- East Tennessee State University
- United States Army