Soluble amyloid triggers a myeloid differentiation factor 88 and interferon regulatory factor 7 dependent neuronal type-1 interferon response in vitro

Journal of Neuroinflammation

Peter John Crack¹  Juliet Marie Taylor¹  Moses Zhang¹  Kate Maree Brody¹  Bevan Scott Main¹  Myles Robert Minter¹ 

[1] Department of Pharmacology and Therapeutics, University of Melbourne, 8th floor, Medical building, Grattan St, Parkville, Melbourne 3010, VIC, Australia

关键词: Alzheimer’s disease;    Amyloid;    IRF7;    Myd88;    Toll-like receptor;    JAK-STAT;    Cytokines;    Neuro-inflammation;    Type-1 interferon;   

Others  :  1227095
DOI  :  10.1186/s12974-015-0263-2

 received in 2014-12-03, accepted in 2015-02-09,  发布年份 2015

【 摘 要 】

Background

Neuro-inflammation has long been implicated as a contributor to the progression of Alzheimer’s disease in both humans and animal models. Type-1 interferons (IFNs) are pleiotropic cytokines critical in mediating the innate immune pro-inflammatory response. The production of type-1 IFNs following pathogen detection is, in part, through the activation of the toll-like receptors (TLRs) and subsequent signalling through myeloid differentiation factor-88 (Myd88) and interferon regulatory factors (IRFs). We have previously identified that neuronal type-1 IFN signalling, through the type-1 interferon alpha receptor-1 (IFNAR1), is detrimental in models of AD. Using an in vitro approach, this study investigated the TLR network as a potential production pathway for neuronal type-1 IFNs in response to Aβ.

Methods

Wildtype and Myd88^−/− primary cultured cortical and hippocampal neurons were treated with 2.5 μM Aβ1-42 for 24 to 72 h or 1 to 10 μM Aβ1-42 for 72 h. Human BE(2)M17 neuroblastoma cells stably expressing an IRF7 small hairpin RNA (shRNA) or negative control shRNA construct were subjected to 7.5 μM Aβ1-42/Aβ42-1 for 24 to 96 h, 2.5 to 15 μM Aβ1-42 for 96 h or 100 ng/ml LPS for 0.5 to 24 h. Q-PCR was used to analyse IFNα, IFNβ, IL-1β, IL-6 and TNFα mRNA transcript levels. Phosphorylation of STAT-3 was detected by Western blot analysis, and cell viability was assessed by MTS assay.

Results

Reduced IFNα, IFNβ, IL-1β, IL-6 and TNFα expression was detected in Aβ1-42-treated Myd88^−/− neurons compared to wildtype cells. This correlated with reduced phosphorylation of STAT-3, a downstream type-1 IFN signalling mediator. Significantly, Myd88^−/− neuronal cultures were protected against Aβ1-42-induced neurotoxicity compared to wildtype as determined by MTS assay. Knockdown of IRF7 in M17 cells was sufficient in blocking IFNα, IFNβ and p-STAT-3 induction to both Aβ1-42 and the TLR4 agonist LPS. M17 IRF7 KD cells were also protected against Aβ1-42-induced cytotoxicity.

Conclusions

This study confirms that the neuronal type-1 IFN response to soluble amyloid is mediated primarily through TLRs. This production is dependent upon Myd88 and IRF7 signalling. This study suggests that targeting this pathway to modulate neuronal type-1 IFN levels may be beneficial in controlling Aβ-induced neurotoxicity.

【 授权许可】

   
2015 Minter et al.; licensee BioMed Central.

【 图 表 】

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