Journal
GLIA
Volume 70, Issue 1, Pages 155-172Publisher
WILEY
DOI: 10.1002/glia.24094
Keywords
HuR inhibitor; LPS; neuroinflammation; RNA binding protein; RNA regulation
Categories
Funding
- National Cancer Institute [R01 CA200624]
- National Institute of Neurological Disorders and Stroke [R21NS111275-01, R01NS092651, RO1NS104339]
- U.S. Department of Veterans Affairs [BX004419]
- University of Alabama at Birmingham O'Neal Comprehensive Cancer Center Neuro-oncology Research Acceleration Fund
Ask authors/readers for more resources
Glial activation with the production of pro-inflammatory mediators is driven by HuR, an RNA regulator that plays a critical role in regulating inflammatory cytokine production in glia. The development of a small molecule inhibitor, SRI-42127, which blocks HuR's translocation, has shown promising effects in suppressing the production of pro-inflammatory mediators and microglial activation, indicating the potential for treating neurological diseases driven by this activation.
Glial activation with the production of pro-inflammatory mediators is a major driver of disease progression in neurological processes ranging from acute traumatic injury to chronic neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Posttranscriptional regulation is a major gateway for glial activation as many mRNAs encoding pro-inflammatory mediators contain adenine- and uridine-rich elements (ARE) in the 3 ' untranslated region which govern their expression. We have previously shown that HuR, an RNA regulator that binds to AREs, plays a major positive role in regulating inflammatory cytokine production in glia. HuR is predominantly nuclear in localization but translocates to the cytoplasm to exert a positive regulatory effect on RNA stability and translational efficiency. Homodimerization of HuR is necessary for translocation and we have developed a small molecule inhibitor, SRI-42127, that blocks this process. Here we show that SRI-42127 suppressed HuR translocation in LPS-activated glia in vitro and in vivo and significantly attenuated the production of pro-inflammatory mediators including IL1 beta, IL-6, TNF-alpha, iNOS, CXCL1, and CCL2. Cytokines typically associated with anti-inflammatory effects including TGF-beta 1, IL-10, YM1, and Arg1 were either unaffected or minimally affected. SRI-42127 suppressed microglial activation in vivo and attenuated the recruitment/chemotaxis of neutrophils and monocytes. RNA kinetic studies and luciferase studies indicated that SRI-42127 has inhibitory effects both on mRNA stability and gene promoter activation. In summary, our findings underscore HuR's critical role in promoting glial activation and the potential for SRI-42127 and other HuR inhibitors for treating neurological diseases driven by this activation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available