Optineurin insufficiency disbalances proinflammatory and anti-inflammatory factors by reducing microglial IFN-β responses

Publication date: Available online 12 July 2018Source: NeuroscienceAuthor(s): Andrea Markovinovic, Tereza Ljutic, Louis-Charles Béland, Ivana MuniticAbstractMutations in a ubiquitin (Ub)-binding adaptor protein optineurin have been found in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with a prominent neuroinflammatory component. Unlike more frequent ALS mutations which cause disease by gaining toxic properties such as aggregation, mutated optineurin is thought to cause disease by loss-of-function, highlighting its neuroprotective role. Optineurin regulates inflammatory signalling by acting as a scaffold for Tank-binding kinase 1 (TBK1) activation and interferon (IFN)-β production in peripheral immune cells. The relevance of this pathway in the CNS is unclear. To investigate IFN-β pathway as a potential mechanism of optineurin-mediated protection from neurodegeneration, we have generated a mouse model in which the Ub-binding region of optineurin was deleted (Optn470T), mimicking C-terminal truncations found in patients. Here we report reduced TBK1 activation and IFN-β production in primary microglia from Optn470T model upon Toll-like receptor (TLR) stimulation. Likewise, we found diminished expression and activation of several transcription factors that support the amplification loop for IFN-β production including STAT1, IRF7 and IRF9. Notably, although optineurin was also reported to block proinflammatory transcription factor NF-κB, normal NF-κB ac...

Source: Neuroscience - July 12, 2018 Category: Neuroscience Source Type: research