{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T05:18:36Z","timestamp":1763875116495,"version":"3.45.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32460898","31760737"],"award-info":[{"award-number":["32460898","31760737"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Xinjiang Production and Construction Corps Agricultural Key and Core Technology Tackling Program","award":["2023AA310"],"award-info":[{"award-number":["2023AA310"]}]},{"name":"Tianshan Talent Program","award":["2024D14009"],"award-info":[{"award-number":["2024D14009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Bacterial meningitis involves complex molecular networks, including microRNA-mediated regulation of inflammatory responses; however, the specific role of Ovis aries microRNA-125b (oar-miR-125b) in this process remains poorly understood. In this study, using a lamb model of Enterococcus faecalis-induced meningitis, we observed significant downregulation of oar-miR-125b, which inversely correlated with its newly identified target, Tumor Necrosis Factor Superfamily Member 4 (TNFSF4). Dual-luciferase reporter assays confirmed that oar-miR-125b directly binds to the 3\u2032 Untranslated Region (3\u2032UTR) of TNFSF4 but not to the 3\u2032UTRs of Kelch Like Family Member 31 (KLHL31) or NF-\u03baB Inhibitor Interacting Ras Like 2 (NKIRAS2). Mechanistically, decreased oar-miR-125b expression relieves its repression of TNFSF4, leading to NF-\u03baB pathway activation and blood\u2013brain barrier disruption. Collectively, our results demonstrate that oar-miR-125b serves as a key anti-inflammatory regulator in bacterial meningitis by targeting TNFSF4 and constraining NF-\u03baB signaling, highlighting its potential as a therapeutic target for attenuating neuroinflammation in meningitis.<\/jats:p>","DOI":"10.3390\/microorganisms13122644","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T08:59:46Z","timestamp":1763715586000},"page":"2644","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Downregulation of oar-miR-125b Drives Blood\u2013Brain Barrier Breakdown Through the TNFSF4\u2013NF-\u03baB Inflammatory Axis in Enterococcus Faecalis Meningitis"],"prefix":"10.3390","volume":"13","author":[{"given":"Longling","family":"Jiao","sequence":"first","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"You","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Borui","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runze","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongjian","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuzhu","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yayin","family":"Qi","sequence":"additional","affiliation":[{"name":"College of Animal Science & Technology, Shihezi University, Shihezi 832003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.jinf.2020.06.064","article-title":"The global meningitis genome partnership","volume":"81","author":"Rodgers","year":"2020","journal-title":"J. Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1001\/jama.2022.20521","article-title":"Progress and Challenges in Bacterial Meningitis","volume":"328","author":"Hasbun","year":"2022","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Amoikon, S.T.L., Diallo, K., Tuo, J.K., Nasir, N., Feteh, V.F., Mzumara, G., Aderoba, A., Jacques, R., Mandal, H., and Jolley, K.A. (2025). In silico and in vitro analyses for the improved diagnosis of bacterial meningitis. Front. Microbiol., 16.","DOI":"10.3389\/fmicb.2025.1655490"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5203","DOI":"10.1007\/s00431-024-05788-w","article-title":"Neurological sequelae after childhood bacterial meningitis","volume":"183","author":"Lempinen","year":"2024","journal-title":"Eur. J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhang, X., Jiang, C., and Zhou, C. (2021). Diagnosis of Enterococcus faecalis meningitis associated with long-term cerebrospinal fluid rhinorrhoea using metagenomics next-generation sequencing: A case report. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06797-y"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7844","DOI":"10.1039\/C9FO01650C","article-title":"Effects of Clostridium butyricum and Enterococcus faecalison growth performance, immune function, intestinal morphology, volatile fatty acids, and intestinal flora in a piglet model","volume":"10","author":"Wang","year":"2019","journal-title":"Food Funct."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Herrera-Hidalgo, L., Fern\u00e1ndez-Rubio, B., Luque-M\u00e1rquez, R., L\u00f3pez-Cort\u00e9s, L.E., Gil-Navarro, M.V., and de Alarc\u00f3n, A. (2023). Treatment of Enterococcus faecalis Infective Endocarditis: A Continuing Challenge. Antibiotics, 12.","DOI":"10.20944\/preprints202303.0033.v1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s15010-024-02372-0","article-title":"Enterococci independently increase the risk for initial antibiotic treatment failure and prolonged hospitalization in adult patients with complicated urinary tract infection: A retrospective cohort study","volume":"53","author":"Zhu","year":"2024","journal-title":"Infection"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Ye, Y., Yang, Q., Zhao, J., Gong, X., Ma, Y., Shi, G., Li, G., and Wu, G. (2025). Enterococci-related healthcare-associated ventriculitis and meningitis: A multicenter retrospective case series from clinical practice. BMC Neurol., 25.","DOI":"10.1186\/s12883-025-04393-0"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e20190062","DOI":"10.1084\/jem.20190062","article-title":"The blood\u2013brain barrier in health and disease: Important unanswered questions","volume":"217","author":"Profaci","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Marzookian, K., Aliakbari, F., Hourfar, H., Sabouni, F., Otzen, D.E., and Morshedi, D. (2025). The neuroprotective effect of human umbilical cord MSCs-derived secretome against \u03b1-synuclein aggregates on the blood-brain barrier. Int. J. Biol. Macromol., 304.","DOI":"10.1016\/j.ijbiomac.2025.140387"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41392-023-01481-w","article-title":"The blood\u2013brain barrier: Structure, regulation and drug delivery","volume":"8","author":"Wu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S1474-4422(23)00377-0","article-title":"Blood\u2013brain barrier dysfunction in multiple sclerosis: Causes, consequences, and potential effects of therapies","volume":"23","author":"Zierfuss","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45663","DOI":"10.1021\/acsomega.4c06546","article-title":"The Impact of the Blood\u2013Brain Barrier and Its Dysfunction in Parkinson\u2019s Disease: Contributions to Pathogenesis and Progression","volume":"9","author":"Muhammad","year":"2024","journal-title":"ACS Omega"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/cpt.353","article-title":"MicroRNAs and cancer resistance: A new molecular plot","volume":"99","author":"Fanini","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.62347\/QWGS2351","article-title":"MiR-125b targeted regulation of MKNK2 inhibits multiple myeloma proliferation and invasion","volume":"16","author":"Tan","year":"2024","journal-title":"Am. J. Transl. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8569","DOI":"10.2147\/CMAR.S259513","article-title":"The miRNA, miR-125b, Inhibited Invasion and Metastasis of Gastric-Cancer Cells by Triggering the STAT3 Signaling Pathway","volume":"12","author":"Xu","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, X., Li, T., Han, Y.-N., Ge, M., Wang, P., Sun, L., Liu, H., Cao, T., Nie, Y., and Fan, D. (2021). miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN. Cancers, 13.","DOI":"10.3390\/cancers13225710"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hou, Y., Zhang, L., Wang, W., Cheng, K., Wang, H., Ji, Y., Su, X., and Hao, M. (2025). Down-regulation of miR-125b by HPV16 E6 might promote cervical cancer progression through TAZ\/TEAD. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1444874"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7865","DOI":"10.1073\/pnas.1200081109","article-title":"MicroRNAs miR-125a and miR-125b constitutively activate the NF-\u03baB pathway by targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20)","volume":"109","author":"Kim","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13567-021-00992-0","article-title":"MiR-125b regulates inflammation in bovine mammary epithelial cells by targeting the NKIRAS2 gene","volume":"52","author":"Luoreng","year":"2021","journal-title":"Vet. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"He, W., Zhao, L., Wang, P., Ren, M., and Han, Y. (2025). MiR-125b-5p ameliorates ox-LDL-induced vascular endothelial cell dysfunction by negatively regulating TNFSF4\/TLR4\/NF-\u03baB signaling. BMC Biotechnol., 25.","DOI":"10.1186\/s12896-025-00944-y"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1600-065X.2009.00766.x","article-title":"The significance of OX40 and OX40L to T-cell biology and immune disease","volume":"229","author":"Croft","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1006\/bbrc.2000.2860","article-title":"Both Amino- and Carboxyl-Terminal Domains of TRAF3 Negatively Regulate NF-\u03baB Activation Induced by OX40 Signaling","volume":"272","author":"Hori","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/08820139.2020.1828912","article-title":"Association of TNFSF4 Gene Polymorphisms and Plasma TNFSF4 Level with Risk of Systemic Lupus Erythematosus in a Chinese Population","volume":"51","author":"Yue","year":"2020","journal-title":"Immunol. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez-Bello, J., Jim\u00e9nez-Morales, S., Barbosa-Cobos, R.E., S\u00e1nchez-Zauco, N., Hern\u00e1ndez-Molina, G., Luria-P\u00e9rez, R., Fragoso, J.M., Cabello-Guti\u00e9rrez, C., and Mont\u00fafar-Robles, I. (2022). TNFSF4 is a risk factor for rheumatoid arthritis but not for primary Sj\u00f6gren\u2019s syndrome in the Mexican population. Immunobiology, 227.","DOI":"10.1016\/j.imbio.2022.152244"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.4049\/jimmunol.1200708","article-title":"Interruption of the OX40\u2013OX40 Ligand Pathway in LDL Receptor\u2013Deficient Mice Causes Regression of Atherosclerosis","volume":"191","author":"Foks","year":"2013","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-024-01364-2","article-title":"Trogocytosis-mediated immune evasion in the tumor microenvironment","volume":"57","author":"Kim","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e011638","DOI":"10.1136\/jitc-2025-011638","article-title":"Dual targeting OX40 and IL-2 receptor enhances antitumor activity through tumor-infiltrating Treg depletion and CD8+ T-cell proliferation","volume":"13","author":"Cao","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_30","first-page":"1","article-title":"Construction of a meningitis infection model in lambs induced by Enterococcus faecalis","volume":"47","author":"Wu","year":"2025","journal-title":"Chin. J. Prev. Vet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Huang, C.-W., Tsai, K.-N., Chen, Y.-S., and Chang, R.-Y. (2021). Differential miRNA Expression Profiling Reveals Correlation of miR125b-5p with Persistent Infection of Japanese Encephalitis Virus. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084218"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dong, K., Chen, F., Wang, L., Lin, C., Ying, M., Li, B., Huang, T., and Wang, S. (2024). iMSC exosome delivers hsa-mir-125b-5p and strengthens acidosis resilience through suppression of ASIC1 protein in cerebral ischemia-reperfusion. J. Biol. Chem., 300.","DOI":"10.1016\/j.jbc.2024.107568"},{"key":"ref_33","first-page":"541","article-title":"Hypoxia preconditioned MSC exosomes attenuate high-altitude cerebral edema via the miR-125a-5p\/RTEF-1 axis to protect vascular endothelial cells","volume":"52","author":"Zuo","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_34","first-page":"225","article-title":"Mechanism of miR-125b-5p in the recovery of brain function after traumatic brain injury","volume":"36","author":"Zhao","year":"2022","journal-title":"Traffic Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1093\/infdis\/jiw449","article-title":"MicroRNA-125b Prevents Cardiac Dysfunction in Polymicrobial Sepsis by Targeting TRAF6-Mediated Nuclear Factor \u03baB Activation and p53-Mediated Apoptotic Signaling","volume":"214","author":"Ma","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2541036","DOI":"10.1080\/19490976.2025.2541036","article-title":"Diarrheal microbiota-derived extracellular vesicles drive intestinal homeostasis dysfunction via miR-125b\/NF-\u03baB-mediated macrophage polarization","volume":"17","author":"Song","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.phrs.2012.02.007","article-title":"Effect of quercetin on inflammatory gene expression in mice liver in vivo\u2014Role of redox factor 1, miRNA-122 and miRNA-125b","volume":"65","author":"Wagner","year":"2012","journal-title":"Pharmacol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1186\/s12964-025-02248-2","article-title":"Breaking the fortress: A mechanistic review of meningitis-causing bacteria breaching tactics in blood brain barrier","volume":"23","author":"Quan","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e595","DOI":"10.1177\/1098612X221125570","article-title":"Use of serum procalcitonin (PCT) level and PCT mRNA expression as a potential clinical biomarker in cats with bacterial and viral infections","volume":"24","author":"Matur","year":"2022","journal-title":"J. Feline Med. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sodero, G., Gentili, C., Mariani, F., Pulcinelli, V., Valentini, P., and Buonsenso, D. (2024). Procalcitonin and Presepsin as Markers of Infectious Respiratory Diseases in Children: A Scoping Review of the Literature. Children, 11.","DOI":"10.3390\/children11030350"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/12\/2644\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T05:18:07Z","timestamp":1763875087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/12\/2644"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["microorganisms13122644"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13122644","relation":{},"ISSN":["2076-2607"],"issn-type":[{"type":"electronic","value":"2076-2607"}],"subject":[],"published":{"date-parts":[[2025,11,21]]}}}