lincRNA-Cox2 regulates NLRP3 inflammasome and autophagy mediated neuroinflammation

Abstract

Inflammasome activation plays key roles in host defense, but also contributes to the pathogenesis of auto-inflammatory, and neurodegenerative diseases. As autophagy is connected with both the innate and adaptive immune systems, autophagic dysfunction is also closely related to inflammation, infection, and neurodegeneration. Here we identify that lincRNA-Cox2, previously known as a mediator of both the activation and repression of immune genes expression in innate immune cells, could bind NF-κB p65 and promote its nuclear translocation and transcription, modulating the expression of inflammasome sensor NLRP3 and adaptor ASC. Knockdown of lincRNA-Cox2 inhibited the inflammasome activation and prevented the lincRNA-Cox2-triggered caspase-1 activation, leading to decreased IL-1β secretion and weakened TIR-domain-containing adapter-inducing interferon-β (TRIF) cleavage, thereby enhancing TRIF-mediated autophagy. Elucidation of the link between lincRNA-Cox2 and the inflammasome-autophagy crosstalk in macrophage and microglia reveals a role for lncRNAs in activation of NLRP3 inflammasome and autophagy, and provides new opportunities for therapeutic intervention in neuroinflammation-dependent diseases.

Genetic Models Reveal cis and trans Immune-Regulatory Activities for lincRNA-Cox2

“…Although there are a number of studies, both by our lab and others, showing that lincRNA-Cox2 promotes and restrains different classes of innate immune gene expression, none have shown the function of this gene in vivo (Carpenter et al, 2013; Covarrubias et al, 2017; Hu et al, 2016; Tong et al, 2016; Xue et al, 2018). Here we expand our knowledge of the role of lincRNA-Cox2 by generating two murine models and multiple macrophage cell lines, which strengthens our earlier findings that lincRNA-Cox2 can inhibit expression of ISGs and enhance pro-inflammatory gene expression.…”

“…KO mice were born at expected Mende- lian frequencies with no obvious developmental abnormalities (Sauvageau et al, 2013). We and others have previously published that lincRNA-Cox2 acts to positively and negatively regulate the expression of distinct classes of innate immune genes (Carpenter et al, 2013; Covarrubias et al, 2017; Hu et al, 2016; Tong et al, 2016; Xue et al, 2018). In those studies, short hairpin RNA (shRNA)-based knockdown of lincRNA- Cox2 reduced the levels of pro-inflammatory cytokines like Interleukin-6 (Il6) in bone-marrow derived macrophages (BMDMs) activated with LPS, whereas a number of interferon- stimulated genes (ISGs) were expressed at higher levels.…”

“…Previous work from our lab and others defined an immune-inducible lincRNA, lincRNA-Cox2 (synonym Ptgs2os2) with broad trans -regulatory activity on inflammatory responses (Carpenter et al, 2013; Covarrubias et al, 2017; Hu et al, 2016; Tong et al, 2016; Xue et al, 2018). In macrophages, where this lincRNA was highly induced upon inflammatory activation, lincRNA-Cox2 functioned to activate and repress distinct classes of innate immune genes (Carpenter et al, 2013).…”

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

“…Very recently, another long noncoding RNA, lincRNA‐Cox2, was reported to be an activator of microglial NLRP3 and autophagy . It binds to NF‐κB p65 and participates in its nuclear translocation and transcription.…”

“…On the other hand, a rare single‐nucleotide polymorphism (SNP) of NLRP3 has been reported to decrease the risk of developing PD, which proves the authentication of the role of NLRP3 inflammasome in development of PD . Moreover, several factors associated with neuroinflammation and dopaminergic neuronal loss, such as mitochondrial generation of ROS, mitophagy, loss of function of dopaminergic receptors, and long noncoding RNA, are emerging that are highly connected with microglial NLRP3 inflammasome activation . Thus, targeting the microglial NLRP3 inflammasome as a potential drug target may provide a new therapeutic avenue for treatment of PD.…”