RESUMO
Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
Assuntos
Astrócitos , Fator 2 Relacionado a NF-E2 , Masculino , Camundongos , Animais , Humanos , Astrócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Sistema Nervoso Central/metabolismo , Oligodendroglia/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Colesterol/metabolismoRESUMO
Failed remyelination underpins neurodegeneration and central nervous system (CNS) dysfunction with aging and progression of neurological diseases, such as multiple sclerosis and Alzheimer's disease. Existing therapies have shown limited efficacy in halting disease progression in humans, highlighting the need to identify pro-remyelination treatments. Microglia are CNS-resident macrophages with critical roles in the regulation of remyelination, representing a promising therapeutic target. However, there are currently no therapeutics which specifically target microglia. Recent studies have revealed that microglia are a heterogenous population with distinct transcriptional states in health and disease conditions, including during remyelination, suggesting functional differences between states. Here, we discuss the potential contributions of different microglia states to degenerative and regenerative processes, examine the potential to target microglia in a state-specific manner to promote remyelination and consider the key issues to be addressed before such therapies can be clinically applied.
