Investigating Gene Expression Effects of Neuregulin-1 (NRG-1) and its Influence on Response to Inflammatory Stimulation with LPS in Microglial Cells In Vitro
Neuregulin-1 (NRG-1) is a potent, endogenous growth factor that has shown promise in treating pathologies with a neuroinflammatory component, but the mechanism through which NRG-1 treatment affects inflammation remains an area of investigation. Studies using NRG-1 as a therapeutic agent in stroke models have indicated that it has neuro-protective and anti-inflammatory properties. In this work we evaluate the role NRG-1 plays in altering inflammatory activation, especially in the context of neuropathology. We examine the effects of NRG-1 treatment on inflammation through in vitro application of NRG-1 to microglia, the main immune cell of the central nervous system (CNS).To execute this work we utilized the high through-put NanoString technology to track gene expression changes and to identify the most prominent features of NRG-1-induced alterations in the inflammatory state of activated SIM-A9 microglia. Stimulation with pro-inflammatory LPS and anti-inflammatory IL-4 were used as benchmarks of canonical microglial activation states to which NRG-1-induced changes were compared.
The most compelling results from this work are that NRG-1 enhances NF-kB and apoptosis pathways that are triggered by pro-inflammatory stimulus and are critical to cell survival. NF-kB influences microglial inflammatory states by tweaking cell sensitivity to apoptotic signaling and increasing gene expression within survival pathways. Specifically, we found that NRG-1 pushes NF-kB signaling towards the non-canonical arm which results in increased expression of genes that encourage immune cell survival. This finding indicates a potentially novel mechanism through which NRG-1 mediates anti-inflammatory outcomes
