Sphingomyelin regulates astrocyte activity by regulating NF-κB signaling via HDAC1/3 expression

Astrocytes comprise approximately 40% of CNS cells and have pivotal roles in brain functions. Under steady-state conditions, astrocytes maintain homeostasis in the CNS through the uptake or release of neurotransmitters. However, in neurodegenerative conditions, astrocytes are activated by inflammatory cytokines, such as interleukin-1alpha (IL-1α) and TNF-α, which are released from activated microglia. Activated astrocytes release several inflammatory cytokines and neurotoxic substances, resulting in neuronal injury. Sphingolipids are a series of bioactive lipids involved in several biological processes, such as apoptosis, inflammatory response, cell cycle, and immune response. SM is a sphingolipid that is a major component of the cellular membrane and is also involved in inflammatory responses. We report that SM promotes IL-1α/TNF-α-induced expressions of representative astrocyte mRNAs and astrocyte activation through the NF-κB pathway. In contrast, reduction of SM by knockdown of sphingomyelin synthase 1 (SMS1) and/or SMS2 suppresses astrocyte activation. Furthermore, removal of SM by the blockade of ceramide transfer protein suppresses astrocyte activation via the induction of histone deacetylase (HDAC) 1 and HDAC3; subsequently, the levels of acetylated p65 (Lys 310) are reduced, leading to the suppression of the NF-κB pathway. Our findings further the understanding of the regulation of astrocyte activation by sphingolipids.