MiR-30a-5p and miR-153-3p regulate LPS-induced neuroinflammatory response and neuronal apoptosis by targeting NeuroD1
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Neurogenic differentiation 1 (NeuroD1) is an essential transcriptionfactor for neuronal differentiation, maturation, and survival,and is associated with inflammation in lipopolysaccharide (LPS)-induced glial cells; however, the concrete mechanisms are stillambiguous. Therefore, we investigated whether NeuroD1-targetingmiRNAs affect inflammation and neuronal apoptosis, as wellas the underlying mechanism. First, we confirmed that miR-30a-5pand miR-153-3p, which target NeuroD1, reduced NeuroD1 expressionin microglia and astrocytes. In LPS-induced microglia,miR-30a-5p and miR-153-3p suppressed pro-inflammatory cytokines,reactive oxygen species, the phosphorylation of c-JunN-terminal kinase, extracellular-signal-regulated kinase (ERK),and p38, and the expression of cyclooxygenase and induciblenitric oxide synthase (iNOS) via the NF-κB pathway. Moreover,miR-30a-5p and miR-153-3p inhibited the expression of NOD-likereceptor pyrin domain containing 3 (NLRP3) inflammasomes,NLRP3, cleaved caspase-1, and IL-1β, which are involved in theinnate immune response. In LPS-induced astrocytes, miR-30a-5pand miR-153-3p reduced ERK phosphorylation and iNOS expressionvia the STAT-3 pathway. Notably, miR-30a-5p exertedgreater anti-inflammatory effects than miR-153-3p. Together,these results indicate that miR-30a-5p and miR-153-3p inhibitMAPK/NF-κB pathway in microglia as well as ERK/STAT-3 pathwayin astrocytes to reduce LPS-induced neuronal apoptosis. This study highlights the importance of NeuroD1 in microgliaand astrocytes neuroinflammation and suggests that it can beregulated by miR-30a-5p and miR-153-3p.
Abstract
Neurogenic differentiation 1 (NeuroD1) is an essential transcriptionfactor for neuronal differentiation, maturation, and survival,and is associated with inflammation in lipopolysaccharide (LPS)-induced glial cells; however, the concrete mechanisms are stillambiguous. Therefore, we investigated whether NeuroD1-targetingmiRNAs affect inflammation and neuronal apoptosis, as wellas the underlying mechanism. First, we confirmed that miR-30a-5pand miR-153-3p, which target NeuroD1, reduced NeuroD1 expressionin microglia and astrocytes. In LPS-induced microglia,miR-30a-5p and miR-153-3p suppressed pro-inflammatory cytokines,reactive oxygen species, the phosphorylation of c-JunN-terminal kinase, extracellular-signal-regulated kinase (ERK),and p38, and the expression of cyclooxygenase and induciblenitric oxide synthase (iNOS) via the NF-κB pathway. Moreover,miR-30a-5p and miR-153-3p inhibited the expression of NOD-likereceptor pyrin domain containing 3 (NLRP3) inflammasomes,NLRP3, cleaved caspase-1, and IL-1β, which are involved in theinnate immune response. In LPS-induced astrocytes, miR-30a-5pand miR-153-3p reduced ERK phosphorylation and iNOS expressionvia the STAT-3 pathway. Notably, miR-30a-5p exertedgreater anti-inflammatory effects than miR-153-3p. Together,these results indicate that miR-30a-5p and miR-153-3p inhibitMAPK/NF-κB pathway in microglia as well as ERK/STAT-3 pathwayin astrocytes to reduce LPS-induced neuronal apoptosis. This study highlights the importance of NeuroD1 in microgliaand astrocytes neuroinflammation and suggests that it can beregulated by miR-30a-5p and miR-153-3p.
참고문헌 (30)
- RansohoffRM, "Innate immunity in the central nervous system", J Clin Invest, 122, pp.1164~1171 (2012)
- Reemst K, "The indispensable roles of microglia and astrocytes during brain development", Front Hum Neurosci, 10, pp.566~ (2016)
- Zhang P, "Synergistic dopaminergic neurotoxicity of manganese and lipopolysaccharide : differential involvement of microglia and astroglia", J Neurochem, 112, pp.434~443 (2010)
- Jha MK, "Functional polarization of neuroglia : implications in neuroinflammation and neurological disorders", Biochem Pharmacol, 103, pp.1~16 (2016)
- Wang S, "Microglia in Alzheimer’s disease : a target for immunotherapy", J Leukoc Biol, 106, pp.219~227 (2019)
- Mosley RL, "Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease", Clin Neurosci Res, 6, pp.261~281 (2006)
- Chen W, "Lentivirus carrying the NeuroD1 gene promotes the conversion from glial cells into neurons in a spinal cord injury model", Brain Res Bull, 135, pp.143~148 (2017)
- Guo Z, "In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model", Cell Stem Cell, 14, pp.188~202 (2014)
- Schwab MH, "Neuronal basic helix-loop-helix proteins(NEX and BETA2", Neuro D)regulate terminal granule cell differentiation in the hippocampus, 2000, pp.20, 3714~3724
- Fu X, "MiR-30a-5p ameliorates spinal cord injury-induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK", ERK signalling, 2018, pp.45, 68~74
- Gao F, "Curcumin alleviates LPS-induced inflammation and oxidative stress in mouse microglial BV2 cells by targeting miR-137-3p", NeuroD1, 2019, pp.9, 38397~38406
- Gu S, "Biological basis for restriction of microRNA targets to the 3’untranslated region in mammalian mRNAs", Nat Struct Mol Biol, 16, pp.144~ (2009)
- Shi Z, "The roles of microRNAs in spinal cord injury", Int J Neurosci, 127, pp.1104~1115 (2017)
- Filipowicz W, "Mechanisms of post-transcriptional regulation by microRNAs : are the answers in sight?", Nat Rev Genet, 9, pp.102~114 (2008)
- Guo Y, "MicroRNAs in microglia : how do microRNAs affect activation, inflammation, polarization of microglia and mediate the interaction between microglia and glioma?", Front Mol Neurosci, 12, pp.125~ (2019)
- Jo EK, "Molecular mechanisms regulating NLRP3 inflammasome activation", Cell Mol Immunol, 13, pp.148~159 (2016)
- Eun-A Kim, "Anti-inflammatory effects of N-cyclooctyl-5-methylthiazol-2-amine hydrobromide on lipopolysaccharide-induced inflammatory response through attenuation of NLRP3 activation in microglial cells", BMB Reports, 54(11), pp.557~562 (2021), 생화학분자생물학회
- Davis BK, "The inflammasome NLRs in immunity, inflammation, and associated diseases", Annu Rev Immunol, 29, pp.707~735 (2011)
- He Y, "Mechanism and regulation of NLRP3 inflammasome activation", Trends Biochem Sci, 41, pp.1012~1021 (2016)
- Jha MK, "Microglia-astrocyte crosstalk : an intimate molecular conversation", The Neuroscientist, 25, pp.227~240 (2019)
- Kim YS, "Matrix metalloproteinase-3 : a novel signaling proteinase from apoptotic neuronal cells that activates microglia", J Neurosci, 25, pp.3701~3711 (2005)
- Bodea LG, "Neurodegeneration by activation of the microglial complement–phagosome pathway", J Neurosci, 34, pp.8546~8556 (2014)
- Gao Z, "Neurod1 is essential for the survival and maturation of adult-born neurons", Nat Neurosci, 12, pp.1090~1092 (2009)
- Greenhill CJ, "IL-6trans-signaling modulates TLR4-dependent inflammatory responses via STAT3", J Immunol, 186, pp.1199~1208 (2011)
- Ryu KY, "Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT", STAT3 signaling, 2019, pp.16, 1~36
- LamkanfiM, "Mechanisms and functions of inflammasomes", Cell, 157, pp.1013~1022 (2014)
- Bauernfeind FG, "Cutting edge : NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression", J Immunol, 183, pp.787~791 (2009)
- Xia Q, "Induction of COX-2-PGE2 synthesis by activation of the MAPK", ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia, 2015, pp.6, e1702~
- Hung CC, "Astrocytic GAP43 induced by the TLR4", NF-κB, J Neurosci, pp.2016, 36[DOI]
- Hartmann K, "Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia", Acta Neuropathol Commun, 7, pp.1~15 (2019)