MIR155HG And MIR155 Synergistically Regulating Microglia Activation And Neuroimmune Response

BackMicroglia-mediated neuroinflammation is one of the most prominent features of neurodegenerative diseases(NDD),including Parkinson’s disease(PD),Alzheimer’s disease(AD),and ALS.Increasing evidence suggests that microglia play both neuroprotective and damaging roles in the occurrence and development of NDD.However,the specific mechanism surrounding the activation of microglia remains unclear.In recent years,an increasing number of studies have shown that microgliamediated central nervous inflammation is an important initiating factor in the formation of NDD cascade.Therefore,elucidating the regulation of microglia function and phenotype seems to be a potential strategy to reverse NDD,which is of great scientific significance for the early detection,diagnosis and treatment of NDD diseases.ObjectiveMicroglia-mediated central inflammatory response plays a key role in the occurrence and development of NDD,but the mechanism of microglia-mediated activation remains unclear.Lnc RNAs and Mi RNAs are important regulators of the NDD and immune inflammatory response.Based on primary microglia sequencing and literature review,the effects and mechanisms of MIR155HG/MIR155-5p on microgliamediated neuroimmune response and neuroinflammation were explored.MethodMolecular level: Further differential gene analysis of Lnc RNA(DEG)was conducted and lnc RNA-MIR155 HG with significant differences was selected by analyzing complete transcripome sequencing of primary microglia cells at resting state and activated by LPS.Down-regulated/overexpressed MIR155HG/MIR155-5P,realtime quantitative PCR(RT-QPCR)and Western blot were used to analyze the expression of mir155HG/MIR155-5p in microglia cells at rest and after activation and its regulatory relationship.Cell level: By down-regulating/overexpressing MIR155HG/MIR155-5P,RT-QPCR,Western blot and flow cytometry were used to detect relevant molecular changes after activation of microglia cells,so as to clarify the role of MIR155HG/MIR155-5P after activation of microglia cells.Animal level: C57 mice downregulated/overexpressed MIR155 HG were constructed by stereotactic injection of lentivirus,followed by an LPS-induced inflammatory model of PD,the expression of MIR155HG/MIR155-5P and the related molecular changes were detected by RT-QPCR,Western blot and immunofluorescence.ResultsAfter activating TLR4,LPS promoted the expression of MIR155HG/MIR155-5P,promoted the activation of microglia cells,and enhanced its neurotoxic effect.MIR155 HG regulates the STAT1 pathway through the type I interferon immune response,thereby altering the expression of interferon response genes(ISG).By targeting SOCS1,MIR155-5p regulates the expression of STAT1 pathway,thereby altering the expression of interferon response genes(ISG)and inflammatory cytokines.ConclusionMIR155HG/MIR155-5P co-regulates the immune response and neuroinflammation after microglia activation,and exacerbates the neurotoxic effect of microglia in neurodegenerative diseases,suggesting that MIR155HG/MIR155-5P can be used as a potential therapeutic target and research direction for neurodegenerative diseases.