Downregulating expression of OPTN elevates neuroinflammation via AIM2 inflammasome- and RIPK1-activating mechanisms in APP/PS1 transgenic mice

Abstract

Background Neuroinflammation is thought to be a cause of Alzheimer’s disease (AD), which is partly caused by inadequate mitophagy. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD. Methods BV2 cells and APP/PS1 transgenic (Tg) mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN in neuroinflammation of AD. Sophisticated molecular technologies including quantitative (q) RT-PCR, western blot, enzyme linked immunosorbent assay (ELISA), co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were employed to reveal the inherent mechanisms. Results As a consequence, key roles of OPTN in regulating neuroinflammation were identified by depressing the activity of absent in melanoma 2 (AIM2) inflammasomes and receptor interacting serine/threonine kinase 1 (RIPK1)-mediated NF-κB inflammatory mechanisms. In detail, we found that expression of OPTN was downregulated, which resulted in activation of AIM2 inflammasomes due to a deficiency in mitophagy in APP/PS1 Tg mice. By ectopic expression, OPTN blocks the effects of Aβ oligomer (Aβo) on activating AIM2 inflammasomes by inhibiting mRNA expression of AIM2 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), leading to a reduction in the active form of caspase-1 and interleukin (IL)-1β in microglial cells. Moreover, RIPK1 was also found to be negatively regulated by OPTN via ubiquitin protease hydrolysis, resulting in the synthesis of IL-1β by activating the transcriptional activity of NF-κB in BV2 cells. As an E3 ligase, the UBAN domain of OPTN binds to the death domain (DD) of RIPK1 to facilitate its ubiquitination. Based on these observations, ectopically expressed OPTN in APP/PS1 Tg mice deactivated microglial cells and astrocytes via the AIM2 inflammasome and RIPK-dependent NF-κB pathways, leading to reduce neuroinflammation. Conclusions These results suggest that OPTN can alleviate neuroinflammation through AIM2 and RIPK1 pathways, suggesting that OPTN deficiency may be a potential factor leading to the occurrence of AD.

Optineurin-mediated mitophagy as a potential therapeutic target for intervertebral disc degeneration

“…We identified differences in the expression of OPTN during the development of IVDD and changes in the expression of OPTN in NPCs subjected to oxidative stress and explored the impact of changes in OPTN expression on NPCs and the potential for OPTN as a therapeutic target for IVDD. We found that the expression of OPTN markedly decreased as IVDD was exacerbated, which is consistent with findings related to the expression of OPTN in degenerative diseases ( Cao et al, 2021 ) and the expression of other mitophagy-related genes in the intervertebral disc ( Chen et al, 2020 ; Hu et al, 2021a ). OPTN expression was substantially increased in cells treated with H 2 O 2 compared with untreated control cells.…”

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…In the late stage of APP/PS1 mouse models, astrocytes also triggered immune signaling and lack of neuroprotection (Orre et al, 2014). Reactive astrocytes induced neuroinflammation and activated the transcriptional activity of NF-κB to induce inflammatory factors (Cao et al, 2021; Figure 2).…”

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

“…Peripheral cells released signal factors to recruit extra cells from the periphery and maintain the activation of microglia and astrocytes, leading to excessive activation of astrocytes, which further damaged surrounding tissues and neurons (Gyoneva and Ransohoff, 2015 ). Additionally, secondary inflammation after CNS injury is the body’s reactive inflammation to the injury, which is different from primary neuroinflammation, such as AD, which is caused by the disorder of normal growth and metabolism in cells (Cao et al, 2021 ).…”