Inflammatory factors reduce neuronal autophagy.

摘要

Neurodegenerative processes are associated with altered neuronal autophagy. Autophagy clears long-lived proteins, organelles and protein aggregates and thus maintaining the normal or enhancing activity of this system has become a common theme in protection from neurodegenerative diseases. In HIV infection as well as other central nervous system (CNS) disorders there is immune activation in the brain, resulting in neuroinflammation. Cytokines drive the inflammatory process, and have a myriad of effects on the brain and specifically neurons. I suspect the autophagy process in neurons is hindered through signaling pathways of released cytokines from immune and glial cells in the brain during HIV infection, resulting in neurodegeneration. I examined the relationship between autophagy and factors produced during neuroinflammation from HIV infection. Pro-inflammatory cytokines were assessed individually on their effects on neuronal autophagy. A neuroblastoma cell culture model was used to assess the effect of cytokines on the autophagy pathway. Measuring autophagy via LC3-II, a marker for autophagosomes, by Western blot analysis, and fluorescent microscopic imaging was used to determine the cytokines' effect on autophagy. Our results reveal that interferon gamma decreases autophagy at the level of autophagy induction. This effect was rescued by a STAT1 inhibitor, fludarabine, suggesting a STAT1 hindrance on neuronal autophagy initiation by IFN-gamma signaling. Additionally IFN-gamma effects on autophagy were verified in primary neurons, confirming the translation of this pathway and effects in a primary neuronal model.