Aβ Induces Neuroinflammation and Microglial M1 Polarization via cGAS-STING-IFITM3 Signaling Pathway in BV-2 Cells

Scheltens P, Blennow K, Breteler MM et al (2016) Alzheimer’s disease. Lancet 388(10043):505–517. https://doi.org/10.1016/S0140-6736(15)01124-1 Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766. https://doi.org/10.1152/physrev.2001.81.2.741 Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. https://doi.org/10.1126/science.1072994 Ozben T, Ozben S (2019) Neuro-inflammation and anti-inflammatory treatment options for Alzheimer’s disease. Clin Biochem 72:87–89. https://doi.org/10.1016/j.clinbiochem.2019.04.001 D’Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25(5):675–683. https://doi.org/10.1016/j.neurobiolaging.2003.12.026 Bolós M, Perea JR, Avila J (2017) Alzheimer’s disease as an inflammatory disease. Biomol Concepts 8(1):37–43. https://doi.org/10.1515/bmc-2016-0029 Escamilla-Tilch M, Filio-Rodríguez G, García-Rocha R et al (2013) The interplay between pathogen-associated and danger-associated molecular patterns: an inflammatory code in cancer? Immunol Cell Biol 91(10):601–610. https://doi.org/10.1038/icb.2013.58 Hopfner KP, Hornung V (2020) Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat Rev Mol Cell Biol 21(9):501–521. https://doi.org/10.1038/s41580-020-0244-x Wu J, Sun L, Chen X et al (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339(6121):826–830. https://doi.org/10.1126/science.1229963 Zhang X, Bai XC, Chen ZJ (2020) Structures and mechanisms in the cGAS-STING innate immunity pathway. Immunity 53(1):43–53. https://doi.org/10.1016/j.immuni.2020.05.013 Chen Q, Sun L, Chen ZJ (2016) Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol 17(10):1142–1149. https://doi.org/10.1038/ni.3558 Kwon OC, Song JJ, Yang Y et al (2021) SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models. EMBO Mol Med 13(4):e13076. https://doi.org/10.15252/emmm.202013076 Liao Y, Cheng J, Kong X et al (2020) HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway. Theranostics 10(21):9644–9662. https://doi.org/10.7150/thno.47651 Compton AA, Bruel T, Porrot F et al (2014) IFITM proteins incorporated into HIV-1 virions impair viral fusion and spread. Cell Host Microbe 16(6):736–747. https://doi.org/10.1016/j.chom.2014.11.001 Rajapaksa US, Jin C, Dong T (2020) Malignancy and IFITM3: friend or foe? Front Oncol 10:593245. https://doi.org/10.3389/fonc.2020.593245 Bailey CC, Zhong G, Huang IC et al (2014) IFITM-Family proteins: the cell’s first line of antiviral defense. Annu Rev Virol 1:261–283. https://doi.org/10.1146/annurev-virology-031413-085537 Everitt AR, Clare S, Pertel T et al (2012) IFITM3 restricts the morbidity and mortality associated with influenza. Nature 484(7395):519–523. https://doi.org/10.1038/nature10921 Mathys H, Adaikkan C, Gao F et al (2017) Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 21(2):366c380. https://doi.org/10.1016/j.celrep.2017.09.039 Hur JY, Frost GR, Wu X et al (2020) The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature 586(7831):735–740. https://doi.org/10.1038/s41586-020-2681-2 Yao AY, Yan R (2002) Activity of Alzheimer’s γ-secretase is linked to changes of interferon-induced transmembrane proteins (IFITM) in innate immunity. Mol Neurodegener 15(1):69. https://doi.org/10.1186/s13024-020-00417-0 Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2):1181–1194. https://doi.org/10.1007/s12035-014-9070-5 Peng Y, Zhuang J, Ying G et al (2020) Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage. J Neuroinflammation 17(1):165. https://doi.org/10.1186/s12974-020-01830-4 Motani K, Kosako H (2010) BioID screening of biotinylation sites using the avidin-like protein tamavidin 2-REV identifies global interactors of stimulator of interferon genes (STING). J Biol Chem 295(32):11174–11183. https://doi.org/10.1074/jbc.RA120.014323 Tarkowski E, Andreasen N, Tarkowski A et al (2003) Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74(9):1200–1205. https://doi.org/10.1136/jnnp.74.9.1200 Shi Y, Holtzman DM (2018) Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol 18(12):759–772. https://doi.org/10.1038/s41577-018-0051-1 Wan D, Jiang W, Hao J (2020) Research advances in how the cGAS-STING pathway controls the cellular inflammatory response. Front Immunol 11:615. https://doi.org/10.3389/fimmu.2020.00615 Reinert LS, Rashidi AS, Tran DN et al (2012) Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. J Clin Invest 131(1):e136824. https://doi.org/10.1172/JCI136824 Jauhari A, Baranov SV, Suofu Y et al (2002) Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Invest 130(6):3124–3136. https://doi.org/10.1172/JCI135026 Lee JD, Woodruff TM (2021) TDP-43 puts the STING in ALS. Trends Neurosci 44(2):81–82. https://doi.org/10.1016/j.tins.2020.12.001 Paul BD, Snyder SH, Bohr VA (2021) Signaling by cGAS-STING in neurodegeneration, neuroinflammation, and aging. Trends Neurosci 44(2):83–96. https://doi.org/10.1016/j.tins.2020.10.008 Li T, Chen ZJ (2018) The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 215(5):1287–1299. https://doi.org/10.1084/jem.20180139 Poddar S, Hyde JL, Gorman MJ et al (2016) The Interferon-Stimulated gene IFITM3 restricts infection and pathogenesis of arthritogenic and encephalitic alphaviruses. J Virol 90(19):8780–8794. https://doi.org/10.1128/JVI.00655-16 Wang X, Wu Z, Li Y et al (2020) p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit japanese encephalitis virus replication. PLoS Pathog 16(10):e1009035. https://doi.org/10.1371/journal.ppat.1009035 Wang H, Tang F, Bian E et al (2020) IFITM3/STAT3 axis promotes glioma cells invasion and is modulated by TGF-β. Mol Biol Rep 47(1):433–441. https://doi.org/10.1007/s11033-019-05146-2 Ibi D, Nagai T, Nakajima A et al (2013) Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice. Glia 61(5):679–693. https://doi.org/10.1002/glia.22461 Guo Y, Jiang F, Kong L et al (2019) Cutting Edge: USP27X Deubiquitinates and stabilizes the DNA sensor cGAS to regulate cytosolic DNA-Mediated signaling. J Immunol 203(8):2049–2054. https://doi.org/10.4049/jimmunol.1900514 Paludan SR, Reinert LS, Hornung V (2019) DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer. Nat Rev Immunol 19(3):141–153. https://doi.org/10.1038/s41577-018-0117-0 Gonugunta VK, Sakai T, Pokatayev V et al (2017) Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep 21(11):3234–3242. https://doi.org/10.1016/j.celrep.2017.11.061