Astrocyte EV-Induced lincRNA-Cox2 Regulates Microglial Phagocytosis: Implications for Morphine-Mediated Neurodegeneration

Abstract

Impairment of microglial functions, such as phagocytosis and/or dysregulation of immune responses, has been implicated as an underlying factor involved in the pathogenesis of various neurodegenerative disorders. Our previous studies have demonstrated that long intergenic noncoding RNA (lincRNA)-Cox2 expression is influenced by nuclear factor κB (NF-κB) signaling and serves as a coactivator of transcriptional factors to regulate the expression of a vast array of immune-related genes in microglia. Extracellular vesicles (EVs) have been recognized as primary facilitators of cell-to-cell communication and cellular regulation. Herein, we show that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) with a subsequent upregulation of lincRNA-Cox2 expression, ultimately resulting in impaired microglial phagocytosis. This was further validated in vivo, wherein inhibition of microglial phagocytic activity was also observed in brain slices isolated from morphine-administrated mice compared with control mice. Additionally, we also showed that intranasal delivery of EVs containing lincRNA-Cox2 siRNA (small interfering RNA) was able to restore microglial phagocytic activity in mice administered morphine. These findings have ramifications for the development of EV-loaded RNA-based therapeutics for the treatment of various disorders involving functional impairment of microglia.

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

“…Once in the brain vesicles likely play a fundamental role in transmitting the infection to other glial cells and perhaps also to neurons in the case of granule cell neuronopathy, a rare complication of JCPyV infection of the brain [43]. Extracellular vesicles are also known to carry an abundance of regulatory molecules including transcription factors and microRNAs that influence the microenvironment of target tissues [44][45][46][47][48][49][50]. The contents of EV derived from JCPyV infected CPE cells, kidney tubule epithelial cells, and primary glial cells has yet to be examined in vitro or in vivo but such studies are likely to shed significant light on the pathogenic mechanisms of JCPyV induced disease.…”

Inflammatory response is modulated by lincRNACox2 via the NF‑κB pathway in macrophages infected by Mycobacterium tuberculosis

“…lincRNACox2 expression is influenced by NF-κB signaling and serves as a coactivator of transcriptional factors to regulate inflammatory responses (28). NF-κB is composed of homo-or heterodimeric complexes of nF-κB subunits including p65, relB, c-rel, p50 and p52 in humans, and is an important regulator of inflammatory and immune responses (29).…”

Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury

“…Some recent studies proposed that exosomes take part in cellto-cell communication. For example, Hu demonstrated that EVs derived from astrocytes exposed to morphine can be taken up by microglial endosomes, leading, in turn, to activation of Toll-like receptor 7 (TLR7) [20]. Sobue reported that the overexpression of MHCI in astrocytes affects microglial proliferation as well as neuronal numbers and spine densities, thereby leading to social and cognitive deficits in mice, possibly via exosomes created by astrocytes [21].…”