Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons

Abstract

Extracellular cold-inducible RNA-binding protein (eCIRP) stimulates microglial in ammation causing neuronal damage during ischemic stroke and is a critical mediator of alcohol-induced cognitive impairment. However, the precise role of eCIRP in mediating neuroin ammation remains unknown. In this study, we report that eCIRP activates neurotoxic cyclin-dependent kinase-5 (Cdk5)/p25 through the induction of IL-6Rα/STAT3 pathway in neurons. Amyloid b (Aβ)-mediated neuronal stress, which is associated with Alzheimer's disease, increased levels of eCIRP released from BV2 microglial cells. The released eCIRP levels from BV2 cells increased 3.2-fold upon stimulation with conditioned medium from Neuro-2a (N2a) cells containing Aβ compared to control N2a supernatant in a time-dependent manner.Stimulation of N2a cells and primary neurons with eCIRP upregulated the neuronal Cdk5 activator p25 expression in a dose-and time-dependent manner. eCIRP directly induced neuronal STAT3 phosphorylation and p25 increase via its novel receptor IL-6Rα. Next, we showed using surface plasmon resonance that eCIRP-derived peptide C23 inhibited the binding of eCIRP to IL-6Rα at 25 mM, with a 40fold increase in equilibrium dissociation constant (K d ) value (from 8.08 x 10 -8 M to 3.43 x 10 -6 M), and completely abrogated the binding at 50 mM. Finally, C23 reversed the eCIRP-induced increase in neuronal STAT3 phosphorylation and p25 levels. In conclusion, the current study demonstrates that upregulation of neuronal IL-6Rα/STAT3/Cdk5 pathway is a key mechanism of eCIRP's role in neuroin ammation and that C23 as a potent inhibitor of this pathway, has translational potential in neurodegenerative pathologies controlled by eCIRP.

Identification of a 6-RBP gene signature for a comprehensive analysis of glioma and ischemic stroke: Cognitive impairment and aging-related hypoxic stress

“…The RBP family of proteins plays an important regulatory role in glioma and IS (Shao et al, 2013 ; Zhou et al, 2014 ; Barbagallo et al, 2018 ; Lan et al, 2020 ; Si et al, 2020 ; Zhang et al, 2020 ; Sharma et al, 2021 ); however, there is a lack of a systematic analysis of the role of RBP in both these diseases. Herein, we describe a set of previously unreported six RBP genes that can be used to predict the prognosis of glioma and diagnostic classification for IS.…”

“…In this context, many RBPs are reportedly associated with a poor prognosis of gliomas (Shao et al, 2013 ; Barbagallo et al, 2018 ; Lan et al, 2020 ). In IS, several RBPs participate in the development and influence the prognoses of these patients by promoting inflammatory reactions (Zhou et al, 2014 ; Sharma et al, 2021 ), increasing cerebrovascular permeability, promoting vasogenic cerebral edema (Ardelt et al, 2017 ), regulating apoptosis (Si et al, 2020 ; Zhang et al, 2020 ), and protecting neurons (Fang et al, 2021 ).…”

Exosome-derived CIRP: An amplifier of inflammatory diseases

“…Supporting this finding, it is well known that CIRP can skew the macrophages towards the M2 phenotype and that using IL-6R antibodies CIRP can inhibit M2 polarization ( 58 ). In neurological diseases, eCIRP activates the IL-6Rα/STAT3/Cdk5 pathway in neurons, inducing neuroinflammation ( 59 ). Combining the above two studies, we can find that IL-6R plays a double-edged sword role in inflammation.…”

“…CIRP is a potential novel mediator of alcohol-induced brain inflammation, leading to local inflammation and neuronal cell damage via the TLR4 pathway ( 75 ). A recent study ( 59 ) reported that eCIRP activated neurotoxic cyclin-dependent kinase-5 (Cdk5)/p25 through the induction of the IL-6Rα/STAT3 pathway in neurons, and C23 subsided the eCIRP-induced increase in neuronal STAT3 phosphorylation and p25 level. Additionally, CIRP may activate TLR4 signaling and further induce NF-κB activation ( 75 ).…”

The role of triggering receptor expressed on myeloid cells-1 (TREM-1) in central nervous system diseases

“…Exposure to Aβ stress increases the release of eCIRP from BV2 microglia. eCIRP mediates neuroinflammation through activation of the IL-6Rα/STAT3/cyclin-dependent kinase-5 (Cdk5) signaling pathway in neurons [ 68 ]. In a middle cerebral artery occlusion (MCAO) model, CIRP and TNF-α levels were observed to be elevated.…”