Optineurin Insufficiency Disbalances Proinflammatory and Anti-inflammatory Factors by Reducing Microglial IFN-β Responses. (15th September 2018)

• Record Type: Journal Article
• Authors: Markovinovic, Andrea; Ljutic, Tereza; Béland, Louis-Charles; Munitic, Ivana
• Is Part Of: Neuroscience. Volume 388(2018)
• Page Start: 139
• Page End: 151
• Publication Date: 2018-09-15
• Subjects: ALS amyotrophic lateral sclerosis -- BMDM bone marrow-derived macrophages -- C9orf72 chromosome 9 open-reading frame 72 -- CNS central nervous system -- CXCL CXC chemokine ligand -- DAMPs damage-associated molecular patterns -- DMEM Dulbecco's Modified Eagle's medium -- FUS fused in sarcoma -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HRP horseradish peroxidase -- Iba1 ionized calcium-binding adapter molecule 1 -- IFN interferon -- IFNAR interferon α/β receptor -- IL interleukin -- IRF interferon regulatory factor -- IκB inhibitor of κΒ -- IKK IκB kinase -- KO knockout -- LC3 microtubule-associated proteins 1A/1B light chain 3 -- LPS lipopolysaccharide -- MEF mouse embryonic fibroblasts -- MS multiple sclerosis -- NEMO NF-κB essential modulator -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NOS2 nitric oxide synthase 2 -- PAMPs pathogen-associated molecular patterns -- PD Parkinson's disease -- Poly (I:C) polyinosinic:polycytidylic acid -- rIFN-β recombinant IFN-β -- RIPK1 receptor-interacting protein kinase 1 -- ROS reactive oxygen species -- RT-PCR real-time polymerase chain reaction -- SOD1 superoxide dismutase 1 -- SQSTM1 sequestosome 1 -- STAT signal transducer and activator of transcription -- TANK TRAF family member-associated NF-κB activator -- TBK1 TANK-binding kinase 1 -- TDP-43 transactive response DNA-binding protein of 43 kDa -- TGF-β transforming growth factor beta -- TLR Toll-like receptor -- TNF tumor necrosis factor; microglia -- IFN-β -- optineurin -- inflammation -- immunomodulation -- neurodegeneration; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.07.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Optineurin-insufficient microglia do not exhibit hyperactivation of inflammatory NF-κB signaling and TNF production. Optineurin upregulates microglial TBK1 activation and IFN-β production in response to TLR stimulation. Diminished IFN-β levels in optineurin-insufficient microglia fail to activate an amplification loop for its production. Disbalanced inflammatory factor profiles in optineurin-insufficient microglia are restored upon IFN-β supplementation. Disbalance of inflammatory factors is a potential disease trigger for neurodegeneration in optineurin mutation carriers. Abstract: 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)-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 (Optn 470T ), mimicking C-terminal truncations found in patients. Here we report reduced TBK1 activation and IFN-β 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-β production including STAT1, IRF7 and IRF9. Notably, although optineurin was also reported to block proinflammatory transcription factor NF-κB, normal NF-κB activation and TNF production were found in Optn 470T microglia. However, expression of both proinflammatory and anti-inflammatory factors distal to IFN-β was diminished, and could be restored upon IFN-β 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-β axis leads to an immune failure in containing neuronal damage, which could predispose to neurodegeneration.