{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:10:35Z","timestamp":1788311435795,"version":"build-2803163510"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Herpes simplex keratitis (HSK) is a blinding disease caused by corneal infection of Herpes simplex virus type 1 (HSV-1). Effective clearance of HSV-1 from the infected cornea is crucial for HSK management. Macrophages play an important part in the innate immune defense against viral infections. This study investigates the immunomodulatory role of NLRP12 in macrophage immune response during HSV-1 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>NLRP12 expression post-infection was assessed in various macrophage cell lines. Overexpression of NLRP12 was achieved by lentiviral transfection, and its effect on HSV-1 replication and immune responses were examined. Mechanistic insights into the role of NLRP12 were explored using immunofluorescence and Western Blot. For <jats:italic>in vivo<\/jats:italic> studies, ocular adoptive transfer of NLRP12-overexpressing bone marrow derived macrophages (BMDMs) was performed. HSV-1 viral loads, HSK symptoms, and macrophage-mediated immune responses were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A significant decrease in NLRP12 expression post-infection was observed in various macrophage cell lines. Overexpression of NLRP12 in macrophages reduced HSV-1 replication. Mechanistically, overexpression of NLRP12 triggered early and robust pyroptosis in response to HSV-1 infection, inducing interleukin (IL)-18 production and activating downstream antiviral responses through the JAK-STAT signaling pathway. In vivo, ocular adoptive transfer of NLRP12-overexpressing BMDMs to mouse corneas alleviated HSK damage and reduced HSV-1 viral loads. NLRP12-overexpressing BMDMs improved antiviral responses in the cornea and promoted the maturation of corneal-infiltrating macrophages and dendritic cells. Additionally, NLRP12-overexpressing BMDMs amplified the adaptive immune response in the submandibular draining lymph nodes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings highlight the role of NLRP12 in macrophage-mediated immune response against HSV-1 infection and suggest its potential for possible immunotherapy for HSK.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2024.1416105","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T06:02:50Z","timestamp":1721887370000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis"],"prefix":"10.3389","volume":"14","author":[{"given":"Jiaxuan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingya","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junpeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PPAT.1003885","article-title":"Malaria-induced NLRP12\/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection","volume":"10","author":"Ataide","year":"2014","journal-title":"PloS Pathog."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS222111398","article-title":"Nod-like receptors: Critical intracellular sensors for host protection and cell death in microbial and parasitic infections","volume":"22","author":"Babamale","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/v12020139","article-title":"Optimized hepatitis E virus (HEV) culture and its application to measurements of HEV infectivity","volume":"12","author":"Capelli","year":"2020","journal-title":"Viruses"},{"key":"B4","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/brainsci7020014","article-title":"NLRP12 inflammasome expression in the rat brain in response to LPS during morphine tolerance","volume":"7","author":"Chang","year":"2017","journal-title":"Brain Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/J.CHOM.2019.02.013","article-title":"NLRP12 regulates anti-viral RIG-I activation via interaction with TRIM25","volume":"25","author":"Chen","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.01631","article-title":"NLRP3, NLRP12, and IFI16 inflammasomes induction and caspase-1 activation triggered by virulent HSV-1 strains are associated with severe corneal inflammatory herpetic disease","volume":"10","author":"Coulon","year":"2019","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/v13091856","article-title":"Advancing our understanding of corneal herpes simplex virus-1 immune evasion mechanisms and future therapeutics","volume":"13","author":"Greenan","year":"2021","journal-title":"Viruses"},{"key":"B8","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.jtos.2021.09.008","article-title":"Host-microbe interactions in cornea","volume":"28","author":"Hazlett","year":"2023","journal-title":"Ocul. Surf."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1048978","article-title":"PKHB1 peptide induces antiviral effects through induction of immunogenic cell death in herpes simplex keratitis","volume":"13","author":"He","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B10","first-page":"85","article-title":"Overview of antiviral medications used in ophthalmology","volume":"33","author":"Hoffman","year":"2020","journal-title":"Community Eye. Health"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.4049\/JIMMUNOL.1700999","article-title":"Nlrp12 mediates adverse neutrophil recruitment during influenza virus infection","volume":"200","author":"Hornick","year":"2018","journal-title":"J. Immunol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.838808","article-title":"Herpes simplex virus 1 induces microglia gasdermin D-dependent pyroptosis through activating the NLR family pyrin domain containing 3 inflammasome","volume":"13","author":"Hu","year":"2022","journal-title":"Front. Microbiol."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2023.101803","article-title":"Pyroptosis and the cellular consequences of gasdermin pores","volume":"69","author":"Huston","year":"2023","journal-title":"Semin. Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5005","DOI":"10.1128\/JVI.00082\u201313","article-title":"Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes","volume":"87","author":"Johnson","year":"2013","journal-title":"J. Virol."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0229570","article-title":"Herpes simplex virus type 1 inflammasome activation in proinflammatory human macrophages is dependent on NLRP3, ASC, and caspase-1","volume":"15","author":"Karaba","year":"2020","journal-title":"PloS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2021.108483","article-title":"Pathobiology and treatment of viral keratitis","volume":"205","author":"Koganti","year":"2021","journal-title":"Exp. Eye. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s00018\u2013018-2938\u20131","article-title":"Pathological processes activated by herpes simplex virus-1 (HSV-1) infection in the cornea","volume":"76","author":"Koujah","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2021.744880","article-title":"A novel role for the regulatory nod-like receptor NLRP12 in anti-dengue virus response","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"6037","DOI":"10.2147\/OTT.S256708","article-title":"Targeting IFN\/STAT1 pathway as a promising strategy to overcome radioresistance","volume":"13","author":"Liu","year":"2020","journal-title":"Onco. Targets Ther."},{"key":"B20","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jtos.2018.10.002","article-title":"Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation","volume":"17","author":"Lobo","year":"2019","journal-title":"Ocular. Surface."},{"key":"B21","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.chom.2017.12.014","article-title":"Herpes simplex virus 1 VP22 inhibits AIM2-dependent inflammasome activation to enable efficient viral replication","volume":"23","author":"Maruzuru","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B22","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/978\u20131-0716\u20132128-8_8","article-title":"Mouse bone marrow cell isolation and macrophage differentiation","volume":"2455","author":"Mendoza","year":"2022","journal-title":"Methods Mol. Biol. (Clifton, N.J.)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5605","DOI":"10.1167\/iovs.07\u20130894","article-title":"Macrophages are important determinants of acute ocular HSV-1 infection in immunized mice","volume":"48","author":"Mott","year":"2007","journal-title":"Invest. Opthalmol. Visual Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1097\/SHK.0000000000001601","article-title":"Tissue-resident macrophages in the control of infection and resolution of inflammation","volume":"55","author":"Mu","year":"2021","journal-title":"Shock"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/J.ACTATROPICA.2021.106202","article-title":"Toxoplasma gondii activates NLRP12 inflammasome pathway in the BALB\/c murine model","volume":"225","author":"Rajabi","year":"2022","journal-title":"Acta Trop."},{"key":"B26","doi-asserted-by":"publisher","first-page":"4310","DOI":"10.7150\/thno.71086","article-title":"Pyroptosis in inflammatory diseases and cancer","volume":"12","author":"Rao","year":"2022","journal-title":"Theranostics"},{"key":"B27","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/sj.cr.7310019","article-title":"Antiviral innate immunity pathways","volume":"16","author":"Seth","year":"2006","journal-title":"Cell Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.jconrel.2023.11.026","article-title":"Targeted delivery of herpes simplex virus glycoprotein D to CD169+ macrophages using ganglioside liposomes alleviates herpes simplex keratitis in mice","volume":"365","author":"Shen","year":"2024","journal-title":"J. Control. Release."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086844","article-title":"Interferon-\u03b3 induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis","volume":"9","author":"Thelemann","year":"2014","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/J.MAM.2020.100887","article-title":"NLRP12 in innate immunity and inflammation","volume":"76","author":"Tuladhar","year":"2020","journal-title":"Mol. Aspects. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1189\/JLB.3RU0514\u2013265RR","article-title":"The multifaceted nature of NLRP12","volume":"96","author":"Tuncer","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/NCOMMS13180","article-title":"Nlrp12 mutation causes C57BL\/6J strain-specific defect in neutrophil recruitment","volume":"7","author":"Ulland","year":"2016","journal-title":"Nat. Commun."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/J.ISCI.2023.106163","article-title":"NLRP12-expressing dendritic cells mediate both dissemination of infection and adaptive immune responses in visceral leishmaniasis","volume":"26","author":"Valadares","year":"2023","journal-title":"IScience"},{"key":"B34","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/J.IMMUNI.2012.07.006","article-title":"The NLRP12 inflammasome recognizes yersinia pestis","volume":"37","author":"Vladimer","year":"2012","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.830699","article-title":"Nectin-1 and non-muscle myosin heavy chain-IIB: major mediators of herpes simplex virus-1 entry into corneal nerves","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"147","DOI":"10.7150\/IJBS.23231","article-title":"NLRP12 promotes mouse neutrophil differentiation through regulation of non-canonical NF-\u03baB and MAPKERK1\/2 signaling","volume":"14","author":"Wang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008335","article-title":"STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection","volume":"16","author":"Wang","year":"2020","journal-title":"PloS Pathog."},{"key":"B38","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.exphem.2018.10.003","article-title":"Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure","volume":"69","author":"Wu","year":"2019","journal-title":"Exp. Hematol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.839585","article-title":"Modulation of macrophage polarization by viruses: turning off\/on host antiviral responses","volume":"13","author":"Yu","year":"2022","journal-title":"Front. Microbiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1073\/PNAS.1317643111","article-title":"Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection","volume":"111","author":"Zaki","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B41","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.imbio.2015.10.001","article-title":"NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-\u03baB or ERK signalling","volume":"221","author":"Zamoshnikova","year":"2016","journal-title":"Immunobiology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00211","article-title":"NLRP3 inflammasome-A key player in antiviral responses","volume":"11","author":"Zhao","year":"2020","journal-title":"Front. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1080\/21505594.2021.1982373","article-title":"Pathogenesis and virulence of herpes simplex virus","volume":"12","author":"Zhu","year":"2021","journal-title":"Virulence"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18061245","article-title":"Transcriptional responses in the murine spleen after Toxoplasma gondii infection: Inflammasome and mucus-associated genes","volume":"18","author":"Znalesniak","year":"2017","journal-title":"Int. J. Mol. Sci."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1416105\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T06:02:55Z","timestamp":1721887375000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2024.1416105\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,25]]},"references-count":44,"alternative-id":["10.3389\/fcimb.2024.1416105"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2024.1416105","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,25]]},"article-number":"1416105"}}