{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:12:39Z","timestamp":1788433959858,"version":"build-2803163510"},"reference-count":81,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ICMR\u2014National Institute of Translational Virology & AIDS Research (NITVAR), Pune, India"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Although persistent neurological sequelae in long COVID are reportedly well associated with neuroinflammation, the underlying regulatory mechanisms remain poorly characterized. Previously, we identified dysregulated microRNA expression, including let-7a-5p, in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike S1-stimulated human microglial cells by RNA sequencing; however, how let-7a-5p regulates the S1-mediated neuroinflammatory processes remains undetermined. In the present study, we examined the functional role of let-7a-5p in alleviating S1-induced microglial inflammation in the CHME3 cell line as well as in human monocyte-derived microglia (MDMi) using a loss- and gain-of-function approach. Functional inhibition of let-7a-5p resulted in mitigating S1-induced inflammatory cytokine release and markers of pyroptosis. Mechanistically, we established SHIP-1 as a direct target of let-7a-5p using luciferase reporter assay validation. Interestingly, we noted upregulated expression of the TLR3 gene alongside TLR2\/4 in S1-stimulated microglia. Although we could not establish exactly how TLR3 is stimulated in S1-induced neuroinflammatory processes, using siRNA-mediated inhibition and a pharmacological inhibitor in both CHME3 cells and MDMi, our study certainly provides evidence of TLR3 involvement during S1-induced microglial inflammation, which needs further investigation. Together, these in vitro findings demonstrate that the let-7a-5p\/SHIP-1 axis regulates S1-induced inflammatory cascades in CHME3 and MDMi cells, providing mechanistic insight into its role in SARS-CoV-2-associated neuroinflammation and warranting further validation in appropriate in vivo\/organoid models.<\/jats:p>","DOI":"10.3390\/ijms27177870","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:10:33Z","timestamp":1788430233000},"page":"7870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Let-7a-5p\/SHIP-1 Axis Drives SARS-CoV-2 Spike-1-Induced Microglial Pyroptosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Puja","family":"Pawar","sequence":"first","affiliation":[{"name":"ICMR National Institute of Translational Virology & AIDS Research, Pune 411026, India"},{"name":"Department of Microbiology, Savitribai Phule Pune University, Pune 411007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha","family":"Ratnakar","sequence":"additional","affiliation":[{"name":"ICMR National Institute of Translational Virology & AIDS Research, Pune 411026, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-806X","authenticated-orcid":false,"given":"Vandana","family":"Saxena","sequence":"additional","affiliation":[{"name":"ICMR National Institute of Translational Virology & AIDS Research, Pune 411026, India"},{"name":"Department of Microbiology, Savitribai Phule Pune University, Pune 411007, India"},{"name":"Faculty of Biological Sciences, Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1093\/cid\/ciab611","article-title":"Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study","volume":"74","author":"Waterboer","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"114868","DOI":"10.1016\/j.bbr.2024.114868","article-title":"The Molecular Fingerprint of Neuroinflammation in COVID-19: A Comprehensive Discussion on Molecular Mechanisms of Neuroinflammation Due to SARS-CoV-2 Antigens","volume":"462","author":"Zayeri","year":"2024","journal-title":"Behav. Brain Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41593-020-00771-8","article-title":"The S1 Protein of SARS-CoV-2 Crosses the Blood-Brain Barrier in Mice","volume":"24","author":"Rhea","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"105131","DOI":"10.1016\/j.nbd.2020.105131","article-title":"The SARS-CoV-2 Spike Protein Alters Barrier Function in 2D Static and 3D Microfluidic in-Vitro Models of the Human Blood-Brain Barrier","volume":"146","author":"Buzhdygan","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Petrovszki, D., Walter, F.R., Vigh, J.P., Kocsis, A., Valkai, S., Deli, M.A., and D\u00e9r, A. (2022). Penetration of the SARS-CoV-2 Spike Protein across the Blood-Brain Barrier, as Revealed by a Combination of a Human Cell Culture Model System and Optical Biosensing. Biomedicines, 10.","DOI":"10.3390\/biomedicines10010188"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/j.chom.2024.11.007","article-title":"Persistence of Spike Protein at the Skull-Meninges-Brain Axis May Contribute to the Neurological Sequelae of COVID-19","volume":"32","author":"Rong","year":"2024","journal-title":"Cell Host Microbe"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia Function in the Central Nervous System During Health and Neurodegeneration","volume":"35","author":"Colonna","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e0109122","DOI":"10.1128\/spectrum.01091-22","article-title":"SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death","volume":"10","author":"Jeong","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111573","DOI":"10.1016\/j.celrep.2022.111573","article-title":"SARS-CoV-2 Infects Neurons and Induces Neuroinflammation in a Non-Human Primate Model of COVID-19","volume":"41","author":"Beckman","year":"2022","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41420-023-01715-4","article-title":"Differential Activation of Programmed Cell Death in Patients with Severe SARS-CoV-2 Infection","volume":"9","author":"Riegler","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s12931-026-03513-9","article-title":"Recombinant SARS-CoV-2 Spike Protein S1 Subunit Upregulates P2\u00d7 7-NLRP3 Leading to Macrophage Pyroptosis Promoting Acute Lung Injury","volume":"27","author":"Lu","year":"2026","journal-title":"Respir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41586-022-04702-4","article-title":"Fc\u03b3R-Mediated SARS-CoV-2 Infection of Monocytes Activates Inflammation","volume":"606","author":"Junqueira","year":"2022","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41586-022-04802-1","article-title":"Inflammasome Activation in Infected Macrophages Drives COVID-19 Pathology","volume":"606","author":"Sefik","year":"2022","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105207","DOI":"10.1016\/j.meegid.2022.105207","article-title":"Evaluation of miR-200c-3p and miR-421-5p Levels during Immune Responses in the Admitted and Recovered COVID-19 Subjects","volume":"98","author":"Abdolahi","year":"2022","journal-title":"Infect. Genet. Evol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111208","DOI":"10.1016\/j.humimm.2024.111208","article-title":"Investigation of the Circulatory microRNAs and Their Involvement in Regulation of Inflammation in Patients with COVID-19","volume":"86","author":"Abbasifard","year":"2025","journal-title":"Hum. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mishra, R., and Banerjea, A.C. (2021). SARS-CoV-2 Spike Targets USP33-IRF9 Axis via Exosomal miR-148a to Activate Human Microglia. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.656700"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1016\/j.nrl.2021.06.005","article-title":"The miRNA Neuroinflammatory Biomarkers in COVID-19 Patients with Different Severity of Illness","volume":"38","author":"Keikha","year":"2023","journal-title":"Neurologia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134329","DOI":"10.1016\/j.ijbiomac.2024.134329","article-title":"An Integrated Bioinformatics Approach Reveals the Potential Role of microRNA-30b-5p and Let-7a-5p during SARS CoV-2 Spike-1 Mediated Neuroinflammation","volume":"277","author":"Pawar","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1002\/jmv.26826","article-title":"Role of Toll-like Receptors in the Pathogenesis of COVID-19","volume":"93","author":"Khanmohammadi","year":"2021","journal-title":"J. Med. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103153","DOI":"10.1016\/j.ebiom.2020.103153","article-title":"Prophylactic Intranasal Administration of a TLR2\/6 Agonist Reduces Upper Respiratory Tract Viral Shedding in a SARS-CoV-2 Challenge Ferret Model","volume":"63","author":"Proud","year":"2021","journal-title":"eBioMedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.1007\/s12035-023-03493-7","article-title":"Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells","volume":"60","author":"Tsilioni","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112189","DOI":"10.1016\/j.celrep.2023.112189","article-title":"SARS-CoV-2 Spike Protein Induces TLR4-Mediated Long-Term Cognitive Dysfunction Recapitulating Post-COVID-19 Syndrome in Mice","volume":"42","author":"Fernandes","year":"2023","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e28561","DOI":"10.1002\/jmv.28561","article-title":"SARS-CoV-2 NSP7 Inhibits Type I and III IFN Production by Targeting the RIG-I\/MDA5, TRIF, and STING Signaling Pathways","volume":"95","author":"Deng","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1186\/s12964-023-01345-4","article-title":"SARS-CoV-2 Primed Platelets-Derived microRNAs Enhance NETs Formation by Extracellular Vesicle Transmission and TLR7\/8 Activation","volume":"21","author":"Liao","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Adhikarla, S.V., Jha, N.K., Goswami, V.K., Sharma, A., Bhardwaj, A., Dey, A., Villa, C., Kumar, Y., and Jha, S.K. (2021). TLR-Mediated Signal Transduction and Neurodegenerative Disorders. Brain Sci., 11.","DOI":"10.3390\/brainsci11111373"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bbi.2021.05.013","article-title":"TLR2- and TLR3-Activated Microglia Induce Different Levels of Neuronal Network Dysfunction in a Context-Dependent Manner","volume":"96","author":"Schilling","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bbi.2022.09.015","article-title":"Human Monocyte-Derived Microglia-like Cell Models: A Review of the Benefits, Limitations and Recommendations","volume":"107","author":"Sargeant","year":"2023","journal-title":"Brain Behav. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1186\/s12974-018-1288-0","article-title":"The Human Microglial HMC3 Cell Line: Where Do We Stand? A Systematic Literature Review","volume":"15","author":"Cappoli","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5077","DOI":"10.2147\/JIR.S474707","article-title":"Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections","volume":"17","author":"Asaba","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12974-023-02786-x","article-title":"SARS-CoV-2 Envelope Protein Triggers Depression-like Behaviors and Dysosmia via TLR2-Mediated Neuroinflammation in Mice","volume":"20","author":"Su","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e21893","DOI":"10.1016\/j.heliyon.2023.e21893","article-title":"SARS-CoV-2 Activates the TLR4\/MyD88 Pathway in Human Macrophages: A Possible Correlation with Strong pro-Inflammatory Responses in Severe COVID-19","volume":"9","author":"Sahanic","year":"2023","journal-title":"Heliyon"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Menezes, F., Palmeira, J.D.F., Oliveira, J.D.S., Arga\u00f1araz, G.A., Soares, C.R.J., N\u00f3brega, O.T., Ribeiro, B.M., and Arga\u00f1araz, E.R. (2024). Unraveling the SARS-CoV-2 Spike Protein Long-Term Effect on Neuro-PASC. Front. Cell Neurosci., 18.","DOI":"10.3389\/fncel.2024.1481963"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"115020","DOI":"10.1016\/j.expneurol.2024.115020","article-title":"SARS-CoV-2 Spike S1 Protein Induces Microglial NLRP3-Dependent Neuroinflammation and Cognitive Impairment in Mice","volume":"383","author":"Jiang","year":"2025","journal-title":"Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/jnc.14645","article-title":"Japanese Encephalitis Virus-Induced Let-7a\/b Interacted with the NOTCH-TLR7 Pathway in Microglia and Facilitated Neuronal Death via Caspase Activation","volume":"149","author":"Mukherjee","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_36","first-page":"2633","article-title":"MicroRNA-let-7a Inhibition Inhibits LPS-induced Inflammatory Injury of Chondrocytes by Targeting IL6R","volume":"20","author":"Sui","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/cmi.2013.51","article-title":"MicroRNA-Let-7a Promotes E2F-Mediated Cell Proliferation and NF\u03baB Activation in Vitro","volume":"11","author":"Chafin","year":"2014","journal-title":"Cell. Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13024-023-00674-9","article-title":"Microglial Function, INPP5D\/SHIP1 Signaling, and NLRP3 Inflammasome Activation: Implications for Alzheimer\u2019s Disease","volume":"18","author":"Terzioglu","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Cond\u00e9, C., Rambout, X., Lebrun, M., Lecat, A., Di Valentin, E., Dequiedt, F., Piette, J., Gloire, G., and Legrand, S. (2012). The Inositol Phosphatase SHIP-1 Inhibits NOD2-Induced NF-\u03baB Activation by Disturbing the Interaction of XIAP with RIP2. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041005"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1096\/fj.201902063R","article-title":"SHIP-1, a Target of miR-155, Regulates Endothelial Cell Responses in Lung Fibrosis","volume":"34","author":"Tang","year":"2020","journal-title":"FASEB J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/cbin.11523","article-title":"Effective Inhibition of miR-330\/SHIP1\/NF-\u03baB Signaling Pathway via miR-330 Sponge Repolarizes Microglia Differentiation","volume":"45","author":"Feng","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Franco, S., Mateu, L., Pluvinet, R., Sanchez-Herrero, J.F., Toledo, R., Sumoy, L., Massanella, M., and Martinez, M.A. (2024). Altered Plasma microRNA Signature in Hospitalized COVID-19 Patients Requiring Oxygen Support. Microorganisms, 12.","DOI":"10.20944\/preprints202312.1840.v2"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Saulle, I., Garziano, M., Cappelletti, G., Limanaqi, F., Strizzi, S., Vanetti, C., Lo Caputo, S., Poliseno, M., Santantonio, T.A., and Clerici, M. (2023). Salivary miRNA Profiles in COVID-19 Patients with Different Disease Severities. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310992"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-1-4939-2547-6_17","article-title":"Dual Luciferase Gene Reporter Assays to Study miRNA Function","volume":"Volume 1296","author":"Salone","year":"2015","journal-title":"Small Non-Coding RNAs"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jneumeth.2017.09.017","article-title":"Magnetofection Is Superior to Other Chemical Transfection Methods in a Microglial Cell Line","volume":"293","author":"Smolders","year":"2018","journal-title":"J. Neurosci. Methods"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.bbi.2021.12.007","article-title":"SARS-CoV-2 Spike S1 Subunit Induces Neuroinflammatory, Microglial and Behavioral Sickness Responses: Evidence of PAMP-like Properties","volume":"100","author":"Frank","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1800401","DOI":"10.1155\/2022\/1800401","article-title":"Conciliatory Anti-Allergic Decoction Attenuates Pyroptosis in RSV-Infected Asthmatic Mice and Lipopolysaccharide (LPS)-Induced 16HBE Cells by Inhibiting TLR3\/NLRP3\/NF-\u03baB\/IRF3 Signaling Pathway","volume":"2022","author":"Chen","year":"2022","journal-title":"J. Immunol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"21425","DOI":"10.1038\/s41598-022-25458-x","article-title":"EV-A71 Induced IL-1\u03b2 Production in THP-1 Macrophages Is Dependent on NLRP3, RIG-I, and TLR3","volume":"12","author":"Huang","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/1742-2094-8-89","article-title":"Poly(I:C) Promotes TNF\u03b1\/TNFR1-Dependent Oligodendrocyte Death in Mixed Glial Cultures","volume":"8","author":"Steelman","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2878","DOI":"10.1038\/s41380-022-01831-0","article-title":"SARS-CoV-2 Drives NLRP3 Inflammasome Activation in Human Microglia through Spike Protein","volume":"28","author":"Albornoz","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41420-021-00428-w","article-title":"SARS-CoV-2 Engages Inflammasome and Pyroptosis in Human Primary Monocytes","volume":"7","author":"Ferreira","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Preissner, K.T., Fischer, S., and Deindl, E. (2020). Extracellular RNA as a Versatile DAMP and Alarm Signal That Influences Leukocyte Recruitment in Inflammation and Infection. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.619221"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e000683","DOI":"10.1161\/JAHA.113.000683","article-title":"Role of Extracellular RNA and TLR3-Trif Signaling in Myocardial Ischemia\u2013Reperfusion Injury","volume":"3","author":"Chen","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Timofeeva, A.M., Aulova, K.S., and Nevinsky, G.A. (2026). Dual Functionality of miRNAs During HIV Infection: From Viral Genome Suppression to Immune Response Modulation. Epigenomes, 10.","DOI":"10.3390\/epigenomes10020039"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"771","DOI":"10.2741\/4917","article-title":"Emerging Roles of microRNAs in the Regulation of Toll-like Receptor (TLR)-Signaling","volume":"26","author":"Banerjee","year":"2021","journal-title":"Front. Biosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nn.3113","article-title":"An Unconventional Role for miRNA: Let-7 Activates Toll-like Receptor 7 and Causes Neurodegeneration","volume":"15","author":"Lehmann","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e00131-24","DOI":"10.1128\/cmr.00131-24","article-title":"Neurological Complications Caused by SARS-CoV-2","volume":"37","author":"Pang","year":"2024","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s10571-023-01444-3","article-title":"Microglial Inflammatory Responses to SARS-CoV-2 Infection: A Comprehensive Review","volume":"44","author":"Dey","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41423-023-01122-w","article-title":"SARS-CoV-2 Immunity in Animal Models","volume":"21","author":"Chen","year":"2024","journal-title":"Cell Mol. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"106182","DOI":"10.1016\/j.neuint.2026.106182","article-title":"Let-7a-5p Targets MAP3K1 to Regulate the MAPK Signaling Pathway in a Depression Model","volume":"197","author":"Fei","year":"2026","journal-title":"Neurochem. Int."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Song, D., Tang, X., Du, J., Tao, K., and Li, Y. (2024). Diazepam Inhibits LPS-Induced Pyroptosis and Inflammation and Alleviates Pulmonary Fibrosis in Mice by Regulating the Let-7a-5p\/MYD88 Axis. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0305409"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13000-021-01089-0","article-title":"Let-7a-5p Regulates the Inflammatory Response in Chronic Rhinosinusitis with Nasal Polyps","volume":"16","author":"Zhang","year":"2021","journal-title":"Diagn. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.jneumeth.2012.05.025","article-title":"A Novel in Vitro Human Microglia Model: Characterization of Human Monocyte-Derived Microglia","volume":"209","author":"Etemad","year":"2012","journal-title":"J. Neurosci. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1038\/srep04957","article-title":"Direct Induction of Ramified Microglia-like Cells from Human Monocytes: Dynamic Microglial Dysfunction in Nasu-Hakola Disease","volume":"4","author":"Ohgidani","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1007\/s12035-024-04289-z","article-title":"Human Microglia\u2013Like Cells Differentiated from Monocytes with GM-CSF and IL-34 Show Phagocytosis of \u03b1-Synuclein Aggregates and C\/EBP\u03b2-Dependent Proinflammatory Activation","volume":"62","author":"Micoli","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"W451","DOI":"10.1093\/nar\/gkl243","article-title":"RNAhybrid: microRNA Target Prediction Easy, Fast and Flexible","volume":"34","author":"Rehmsmeier","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1261\/rna.5248604","article-title":"Fast and Effective Prediction of microRNA\/Target Duplexes","volume":"10","author":"Rehmsmeier","year":"2004","journal-title":"RNA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1101\/gr.229102","article-title":"The Human Genome Browser at UCSC","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"D140","DOI":"10.1093\/nar\/gkj112","article-title":"miRBase: microRNA Sequences, Targets and Gene Nomenclature","volume":"34","author":"Grocock","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.bbrc.2011.12.129","article-title":"Reduced expression of Kr\u00fcppel-like factor 17 is related to tumor growth and poor prognosis in lung adenocarcinoma","volume":"418","author":"Cai","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ali, M.F., Dasari, H., Van Keulen, V.P., and Carmona, E.M. (2017). Canonical Stimulation of the NLRP3 Inflammasome by Fungal Antigens Links Innate and Adaptive B-Lymphocyte Responses by Modulating IL-1\u03b2 and IgM Production. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01504"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3780","DOI":"10.4049\/jimmunol.176.6.3780","article-title":"Regulation of IL-1 family cytokines IL-1alpha, IL-1 receptor antagonist, and IL-18 by 1,25-dihydroxyvitamin D3 in primary keratinocytes","volume":"176","author":"Kong","year":"2006","journal-title":"J. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1093\/toxsci\/kfx152","article-title":"Chalcogenozidovudine Derivatives With Antitumor Activity: Comparative Toxicities in Cultured Human Mononuclear Cells","volume":"160","author":"Ecker","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/toxsci\/kfy280","article-title":"Exposure to 1,2-Dichloropropane Upregulates the Expression of Activation-Induced Cytidine Deaminase (AID) in Human Cholangiocytes Co-Cultured With Macrophages","volume":"168","author":"Zong","year":"2019","journal-title":"Toxicol. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Chen, R.-F., Wang, L., Cheng, J.-T., and Yang, K.D. (2012). Induction of IFN\u03b1 or IL-12 depends on differentiation of THP-1 cells in dengue infections without and with antibody enhancement. BMC Infect. Dis., 12.","DOI":"10.1186\/1471-2334-12-340"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-1-4939-8931-7_5","article-title":"Relative Human Telomere Length Quantification by Real-Time PCR","volume":"1896","author":"Vasilishina","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12974-017-0798-5","article-title":"Activation of human B cells negatively regulates TGF-\u03b21 production","volume":"14","author":"Molnarfi","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"104625","DOI":"10.1016\/j.archoralbio.2019.104625","article-title":"Initial periodontal treatment affects nucleotide-binding domain leucine-rich repeat-containing protein 3 inflammasome priming in peripheral blood mononuclear cells","volume":"110","author":"Higuchi","year":"2020","journal-title":"Arch. Oral Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00441-015-2118-7","article-title":"Activation of the NLRP3\/caspase-1 inflammasome in human dental pulp tissue and human dental pulp fibroblasts","volume":"361","author":"Jiang","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1007\/s11010-021-04157-7","article-title":"Human cardiac fibroblasts produce pro-inflammatory cytokines upon TLRs and RLRs stimulation","volume":"476","author":"Li","year":"2021","journal-title":"Mol. Cell Biochem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/JPER.20-0285","article-title":"The role of PHF8 and TLR4 in osteogenic differentiation of periodontal ligament cells in inflammatory environment","volume":"92","author":"Liu","year":"2021","journal-title":"J. Periodontol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7870\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:13:40Z","timestamp":1788430420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":81,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177870"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177870","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]}}}