| First Author | Markovinovic A | Year | 2018 |
| Journal | Neuroscience | Volume | 388 |
| Pages | 139-151 | PubMed ID | 30017954 |
| Mgi Jnum | J:267043 | Mgi Id | MGI:6257250 |
| Doi | 10.1016/j.neuroscience.2018.07.007 | Citation | Markovinovic A, et al. (2018) Optineurin Insufficiency Disbalances Proinflammatory and Anti-inflammatory Factors by Reducing Microglial IFN-beta Responses. Neuroscience 388:139-151 |
| abstractText | Mutations 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 signaling by acting as a scaffold for Tank-binding kinase 1 (TBK1) activation and interferon (IFN)-beta production in peripheral immune cells. The relevance of this pathway in the CNS is unclear. To investigate IFN-beta 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 (Optn(470T)), mimicking C-terminal truncations found in patients. Here we report reduced TBK1 activation and IFN-beta production in primary microglia from Optn(470T) 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-beta production including STAT1, IRF7 and IRF9. Notably, although optineurin was also reported to block proinflammatory transcription factor NF-kappaB, normal NF-kappaB activation and TNF production were found in Optn(470T) microglia. However, expression of both proinflammatory and anti-inflammatory factors distal to IFN-beta was diminished, and could be restored upon IFN-beta supplementation. Taken together with the recent discoveries of TBK1 mutations as an important genetic factor in ALS, our results open up the possibility that disruption of optineurin/TBK1-mediated IFN-beta axis leads to an immune failure in containing neuronal damage, which could predispose to neurodegeneration. |
