{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:07:14Z","timestamp":1791846434033,"version":"4.3.4"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"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 Dev. Biol."],"abstract":"<jats:p>Periodontitis is a chronic inflammatory oral disease that affects almost half of the adult population. NF-\u03baB activator 1 (Act1) is mainly expressed in immune cells, including macrophages, and modulates immune cells\u2019 function to regulate inflammation in inflammatory diseases. Macrophages play a vital role in the pathophysiology of periodontitis. However, the effect of macrophage-specific Act1 on periodontitis has not been investigated yet. This study aims to unravel the role of macrophage-specific Act1 on the pathophysiology of periodontitis. The expression of Act1 in healthy and periodontitis periodontal tissue was confirmed by immunohistochemistry. Macrophage-specific Act1 expression downregulated (anti-Act1) mice were developed by inserting anti-Act1 antisense oligonucleotides after the CD68 promoter of C57BL\/6 mice. Ligature-induced periodontitis (LIP) was induced in anti-Act1 mice and wildtype mice. Micro-CT, histology, and TRAP staining analyzed the periodontal tissue status, alveolar bone loss, and osteoclast numbers. Immunohistochemistry, RT-qPCR, and ELISA analyzed the inflammatory cells infiltration, expression of inflammatory cytokines, and M1\/M2 macrophage polarization. mRNA sequencing of <jats:italic>in vitro<\/jats:italic> bacterial lipopolysaccharide (LPS)-treated peritoneal macrophages analyzed the differentially expressed genes in anti-Act1 mice during inflammation. Anti-Act1 mice showed aggravated periodontitis and alveolar bone loss compared to wildtype. Periodontitis-affected periodontal tissue (PAPT) of anti-Act1 mice showed a higher degree of macrophage infiltration, and M1 macrophage polarization compared to wildtype. Levels of pro-inflammatory cytokines (IL-1\u03b2, IL-6, and TNF\u03b1), and macrophage activity-related factors (CCL2, CCL3, and CCL4) were robustly high in PAPT of anti-Act1 mice compared to wildtype. mRNA sequencing and KEGG analysis showed activated TNF\/NF-\u03baB signaling in LPS-treated macrophages from anti-Act1 mice. <jats:italic>In vitro<\/jats:italic> studies on LPS-treated peritoneal macrophages from anti-act1 mice showed a higher degree of cell migration and expression of inflammatory cytokines, macrophage activity-related factors, M1 macrophage-related factors, and TNF\/NF-\u03baB signaling related P-p65 protein. In conclusion, downregulation of macrophage-specific Act1 aggravated periodontitis, alveolar bone loss, macrophage infiltration, inflammation, and M1 macrophage polarization. Furthermore, LPS-treated macrophages from anti-Act1 mice activated TNF\/NF-\u03baB signaling. These results indicate the distinct role of macrophage-specific Act1 on the pathophysiology of periodontitis possibly via TNF\/NF-\u03baB signaling.<\/jats:p>","DOI":"10.3389\/fcell.2021.628139","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T06:22:25Z","timestamp":1614838945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Downregulation of Macrophage-Specific Act-1 Intensifies Periodontitis and Alveolar Bone Loss Possibly via TNF\/NF-\u03baB Signaling"],"prefix":"10.3389","volume":"9","author":[{"given":"Janak L.","family":"Pathak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhitong","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongliang","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxian","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luxi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.jim.2013.05.002","article-title":"Optimization of the ligature-induced periodontitis model in mice.","volume":"394","author":"Abe","year":"2013","journal-title":"J. Immunol. Methods"},{"key":"B2","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1111\/iej.12196","article-title":"The role of IL-6 on apical periodontitis: a systematic review.","volume":"47","author":"Azuma","year":"2014","journal-title":"Int. Endod. J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nrmicro2337","article-title":"Periodontitis: a polymicrobial disruption of host homeostasis.","volume":"8","author":"Darveau","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/ar4071","article-title":"New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis.","volume":"14","author":"Doyle","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"B5","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1177\/0022034512457373","article-title":"Prevalence of periodontitis in adults in the United States: 2009 and 2010.","volume":"91","author":"Eke","year":"2012","journal-title":"J. Dent. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1177\/0022034520939029","article-title":"SETD1 and NF-kappaB regulate periodontal inflammation through H3K4 trimethylation.","volume":"99","author":"Francis","year":"2020","journal-title":"J. Dent. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nbt.3172","article-title":"Ballgown bridges the gap between transcriptome assembly and expression analysis.","volume":"33","author":"Frazee","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1034\/j.1600-051x.2002.290206.x","article-title":"IL-8 and TNF-alpha from peripheral neutrophils and acute-phase proteins in periodontitis.","volume":"29","author":"Fredriksson","year":"2002","journal-title":"J. Clin. Periodontol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1111\/prd.12201","article-title":"Nonsurgical and surgical treatment of periodontitis: how many options for one disease?","volume":"75","author":"Graziani","year":"2017","journal-title":"Periodontol. 2000"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.it.2013.09.001","article-title":"Immunomicrobial pathogenesis of periodontitis: keystones, pathobionts, and host response.","volume":"35","author":"Hajishengallis","year":"2014","journal-title":"Trends Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1038\/s41590-019-0526-7","article-title":"Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1.","volume":"20","author":"Hasegawa","year":"2019","journal-title":"Nat. Immunol."},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1186\/s13287-020-01607-9","article-title":"Mechanical load-induced H2S production by periodontal ligament stem cells activates M1 macrophages to promote bone remodeling and tooth movement via STAT1.","volume":"11","author":"He","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1111\/j.1600-051x.2009.01517.x","article-title":"Prevalence of periodontal disease and treatment demands based on a german dental survey (DMS IV).","volume":"37","author":"Holtfreter","year":"2010","journal-title":"J. Clin. Periodontol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"7","DOI":"10.4248\/ijos11006","article-title":"Oral health in China\u2013trends and challenges.","volume":"3","author":"Hu","year":"2011","journal-title":"Int. J. Oral Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.immuni.2010.03.004","article-title":"Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis.","volume":"32","author":"Kang","year":"2010","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1177\/0022034514552491","article-title":"Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression.","volume":"93","author":"Kassebaum","year":"2014","journal-title":"J. Dent. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1089\/cmb.2017.0096","article-title":"cutPrimers: a new tool for accurate cutting of primers from reads of targeted next generation sequencing.","volume":"24","author":"Kechin","year":"2017","journal-title":"J. Comput. Biol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12520","article-title":"Olive (Olea europaea) leaf extract alters the cytokine profile of leishmania major-infected macrophages: new insight into the underlying mechanism.","volume":"40","author":"Kheirandish","year":"2018","journal-title":"Parasite Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements.","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"B20","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.cyto.2018.06.013","article-title":"From macrophage to osteoclast\u2013how metabolism determines function and activity.","volume":"112","author":"Kubatzky","year":"2018","journal-title":"Cytokine"},{"key":"B21","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1111\/ddg.12165","article-title":"Lupus erythematosus. part I: epidemiology, genetics and immunology.","volume":"11","author":"Kunz","year":"2013","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"B22","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.joca.2008.11.011","article-title":"Proinflammatory cytokines inhibit osteogenic differentiation from stem cells: implications for bone repair during inflammation.","volume":"17","author":"Lacey","year":"2009","journal-title":"Osteoarthritis Cartilage"},{"key":"B23","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cyto.2007.09.015","article-title":"Act1 modulates autoimmunity through its dual functions in CD40L\/BAFF and IL-17 signaling.","volume":"41","author":"Li","year":"2008","journal-title":"Cytokine"},{"key":"B24","doi-asserted-by":"publisher","first-page":"10489","DOI":"10.1073\/pnas.160265197","article-title":"Act1, an NF-kappa B-activating protein.","volume":"97","author":"Li","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"B25","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.ejcb.2011.10.001","article-title":"The role of TNF and fas dependent signaling in animal models of inflammatory liver injury and liver cancer.","volume":"91","author":"Liedtke","year":"2012","journal-title":"Eur. J. Cell Biol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000382","article-title":"Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.","volume":"2","author":"Liu","year":"2009","journal-title":"Sci. Signal."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188317","article-title":"NF-kappaB pathways are involved in M1 polarization of RAW 264.7 macrophage by polyporus polysaccharide in the tumor microenvironment.","volume":"12","author":"Liu","year":"2017","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1007\/s10753-020-01263-4","article-title":"Heparin-binding protein enhances NF-kappaB pathway-mediated inflammatory gene transcription in M1 macrophages via lactate.","volume":"44","author":"Lu","year":"2020","journal-title":"Inflammation"},{"key":"B29","article-title":"Isolation, processing and analysis of murine gingival cells.","volume":"77","author":"Mizraji","year":"2013","journal-title":"J. Vis. Exp."},{"key":"B30","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1016\/s0968-0004(03)00067-7","article-title":"The STIR-domain superfamily in signal transduction, development and immunity.","volume":"28","author":"Novatchkova","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1155\/2018\/8917804","article-title":"Macrophage polarization in chronic inflammatory diseases: killers or builders?","volume":"2018","author":"Parisi","year":"2018","journal-title":"J. Immunol. Res."},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1242\/jcs.216267","article-title":"Common signalling pathways in macrophage and osteoclast multinucleation.","volume":"131","author":"Pereira","year":"2018","journal-title":"J. Cell Sci."},{"key":"B33","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nbt.3122","article-title":"StringTie enables improved reconstruction of a transcriptome from RNA-seq reads.","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/978-1-4939-2929-0_6","article-title":"Isolation, culture, and polarization of murine bone marrow-derived and peritoneal macrophages.","volume":"1339","author":"Pineda-Torra","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3334","DOI":"10.1002\/art.27653","article-title":"The adaptor protein CIKS\/ACT1 is necessary for collagen-induced arthritis, and it contributes to the production of collagen-specific antibody.","volume":"62","author":"Pisitkun","year":"2010","journal-title":"Arthritis Rheum."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1002\/eji.200738113","article-title":"Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjogren\u2019s syndrome.","volume":"38","author":"Qian","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/ni1439","article-title":"The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.","volume":"8","author":"Qian","year":"2007","journal-title":"Nat. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"9386","DOI":"10.1073\/pnas.142294499","article-title":"Role of NF kappa B activator Act1 in CD40-mediated signaling in epithelial cells.","volume":"99","author":"Qian","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1016\/j.bone.2009.12.030","article-title":"Evidences of the cooperative role of the chemokines CCL3, CCL4 and CCL5 and its receptors CCR1+ and CCR5+ in RANKL+ cell migration throughout experimental periodontitis in mice.","volume":"46","author":"Repeke","year":"2010","journal-title":"Bone"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.compbiomed.2016.09.017","article-title":"Improving information retrieval in functional analysis.","volume":"79","author":"Rodriguez","year":"2016","journal-title":"Comput. Biol. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"4323","DOI":"10.12659\/msm.898422","article-title":"Peripheral blood leukocytes interleukin-1 beta (IL-1beta) cytokine hyper-reactivity in chronic periodontitis.","volume":"22","author":"Sakalauskiene","year":"2016","journal-title":"Med. Sci. Monit."},{"key":"B42","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.atherosclerosis.2016.05.029","article-title":"TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-\/-) mice.","volume":"252","author":"Sakamuri","year":"2016","journal-title":"Atherosclerosis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01482","article-title":"Rheumatoid synovial fluids regulate the immunomodulatory potential of adipose-derived mesenchymal stem cells through a TNF\/NF-kappaB-dependent mechanism.","volume":"10","author":"Sayegh","year":"2019","journal-title":"Front. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2340","DOI":"10.1902\/jop.2008.080192","article-title":"Systemic inflammation markers in patients with aggressive periodontitis: a pilot study.","volume":"79","author":"Shi","year":"2008","journal-title":"J. Periodontol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1002\/jlb.1ru0818-310r","article-title":"Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis.","volume":"105","author":"Sima","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3155","DOI":"10.4049\/jimmunol.1002790","article-title":"T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation.","volume":"187","author":"Swaidani","year":"2011","journal-title":"J. Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.4049\/jimmunol.182.3.1631","article-title":"The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation.","volume":"182","author":"Swaidani","year":"2009","journal-title":"J. Immunol."},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1038\/sdata.2018.289","article-title":"A protein-protein interaction map of the TNF-induced NF-kappaB signal transduction pathway.","volume":"5","author":"Van Quickelberghe","year":"2018","journal-title":"Sci. Data"},{"key":"B49","doi-asserted-by":"publisher","first-page":"4571","DOI":"10.1007\/s00784-020-03324-2","article-title":"Macrophages skew towards M1 profile through reduced CD163 expression in symptomatic apical periodontitis.","volume":"24","author":"Veloso","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"B50","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of disease study 2010.","volume":"380","author":"Vos","year":"2012","journal-title":"Lancet"},{"key":"B51","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/ni.2479","article-title":"The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90.","volume":"14","author":"Wang","year":"2013","journal-title":"Nat. Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus\u2013infected pneumonia in Wuhan, China.","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"B53","first-page":"1","article-title":"Targeted suppression of macrophage Act1 inhibits the lung metastasis of melanoma cells in mice.","volume":"29","author":"Wang","year":"2019","journal-title":"Chin. J. Comp. Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.intimp.2015.01.007","article-title":"Subcutaneous vaccination with Porphyromonas gingivalis ameliorates periodontitis by modulating Th17\/Treg imbalance in a murine model.","volume":"25","author":"Wang","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00593","article-title":"SLIT2 overexpression in periodontitis intensifies inflammation and alveolar bone loss, possibly via the activation of MAPK pathway.","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/s0006-291x(02)00887-2","article-title":"Identification of alternatively spliced Act1 and implications for its roles in oncogenesis.","volume":"296","author":"Xia","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B57","doi-asserted-by":"crossref","DOI":"10.1016\/j.chom.2017.06.014","article-title":"Diabetes enhances IL-17 expression and alters the oral microbiome to increase its pathogenicity.","volume":"22","author":"Xiao","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B58","doi-asserted-by":"publisher","first-page":"4698","DOI":"10.1002\/jcp.29348","article-title":"YAP1 inhibits the induction of TNF-\u03b1-stimulated bone-resorbing mediators by suppressing the NF-\u03baB signaling pathway in MC3T3-E1 cells.","volume":"235","author":"Yang","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.archoralbio.2017.03.006","article-title":"Enhanced activity of macrophage M1\/M2 phenotypes in periodontitis.","volume":"96","author":"Yang","year":"2018","journal-title":"Arch. Oral Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1093\/abbs\/gmx092","article-title":"Osteoclast stimulatory transmembrane protein induces a phenotypic switch in macrophage polarization suppressing an M1 pro-inflammatory state.","volume":"49","author":"Yuan","year":"2017","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"B61","article-title":"Act1 is a negative regulator in T and B cells via direct inhibition of STAT3.","volume":"9","author":"Zhang","year":"2018","journal-title":"Nat. Commun."},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00718","article-title":"Bilobalide alleviated dextran sulfate sodium-induced experimental colitis by inhibiting M1 macrophage polarization through the NF-kappaB signaling pathway.","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3402\/gha.v7.24503","article-title":"Prevalence and predictors for periodontitis among adults in China, 2010.","volume":"7","author":"Zhang","year":"2014","journal-title":"Glob. Health Action"},{"key":"B64","doi-asserted-by":"publisher","first-page":"558","DOI":"10.7150\/ijms.40918","article-title":"PDLSCs regulate angiogenesis of periodontal ligaments via VEGF transferred by exosomes in periodontitis.","volume":"17","author":"Zhang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1111\/odi.13167","article-title":"M1 macrophages regulate TLR4\/AP1 via paracrine to promote alveolar bone destruction in periodontitis.","volume":"25","author":"Zhu","year":"2019","journal-title":"Oral Dis."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.628139\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T06:22:41Z","timestamp":1614838961000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.628139\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":65,"alternative-id":["10.3389\/fcell.2021.628139"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.628139","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]},"article-number":"628139"}}