{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:52:55Z","timestamp":1793332375496,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DE015254, DE024716, DE024153,DE026152"],"award-info":[{"award-number":["DE015254, DE024716, DE024153,DE026152"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2017-01198"],"award-info":[{"award-number":["2017-01198"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Aim: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a modifier of local and systemic inflammation. There is clinical evidence implicating TREM-1 in the pathogenesis of periodontitis. However, a cause-and-effect relationship has yet to be demonstrated, as is the underlying mechanism. The aim of this study was to elucidate the role of TREM-1 using the murine ligature-induced periodontitis model. Methods: A synthetic antagonistic LP17 peptide or sham control was microinjected locally into the palatal gingiva of the ligated molar teeth. Results: Mice treated with the LP17 inhibitor developed significantly less bone loss as compared to sham-treated mice, although there were no differences in total bacterial load on the ligatures. To elucidate the impact of LP17 on the host response, we analyzed the expression of a number of immune-modulating genes. The LP17 peptide altered the expression of 27\/92 genes \u2265 two-fold, but only interleukin (IL)-17A was significantly downregulated (4.9-fold). Importantly, LP17 also significantly downregulated the receptor activator of nuclear factor kappa-B-ligand (RANKL) to osteoprotegerin (OPG) ratio that drives osteoclastic bone resorption in periodontitis. Conclusion: Our findings show for the first time that TREM-1 regulates the IL-17A-RANKL\/OPG axis and bone loss in experimental periodontitis, and its therapeutic blockade may pave the way to a novel treatment for human periodontitis.<\/jats:p>","DOI":"10.3390\/jcm8101579","type":"journal-article","created":{"date-parts":[[2019,10,2]],"date-time":"2019-10-02T08:17:54Z","timestamp":1570004274000},"page":"1579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss"],"prefix":"10.3390","volume":"8","author":[{"given":"Nagihan","family":"Bostanci","sequence":"first","affiliation":[{"name":"Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, 14104 Huddinge, Sweden"},{"name":"Center of Dental Medicine, University of Z\u00fcrich, 8032 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiharu","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-0653","authenticated-orcid":false,"given":"Georgios N.","family":"Belibasakis","sequence":"additional","affiliation":[{"name":"Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, 14104 Huddinge, Sweden"},{"name":"Center of Dental Medicine, University of Z\u00fcrich, 8032 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7392-8852","authenticated-orcid":false,"given":"George","family":"Hajishengallis","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.molmed.2014.11.004","article-title":"Polymicrobial synergy and dysbiosis in inflammatory disease","volume":"21","author":"Lamont","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/prd.12181","article-title":"Revisiting the Page & Schroeder model: The good, the bad and the unknowns in the periodontal host response 40 years later","volume":"75","author":"Hajishengallis","year":"2017","journal-title":"Periodontol. 2000"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1177\/0022034510376402","article-title":"Destructive and Protective Roles of Cytokines in Periodontitis: A Re-appraisal from Host Defense and Tissue Destruction Viewpoints","volume":"89","author":"Garlet","year":"2010","journal-title":"J. Dent. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1177\/154405910608500704","article-title":"Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis","volume":"85","author":"Lerner","year":"2006","journal-title":"J. Dent. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1600-051X.2011.01810.x","article-title":"The RANKL-OPG system in clinical periodontology","volume":"39","author":"Belibasakis","year":"2012","journal-title":"J. Clin. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.cyto.2011.03.009","article-title":"The RANKL-OPG system is differentially regulated by supragingival and subgingival biofilm supernatants","volume":"55","author":"Belibasakis","year":"2011","journal-title":"Cytokine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"181","DOI":"10.3121\/cmr.2.3.181","article-title":"Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 as a Marker of Microbial Infection","volume":"2","author":"Gibot","year":"2004","journal-title":"Clin. Med. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S397","DOI":"10.1086\/374754","article-title":"TREM-1 (Triggering Receptor Expressed on Myeloid Cells): A New Player in Acute Inflammatory Responses","volume":"187","author":"Colonna","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1172\/JCI30602","article-title":"TREM-1\u2013expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases","volume":"117","author":"Schenk","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1084\/jem.20040708","article-title":"A Soluble Form of the Triggering Receptor Expressed on Myeloid Cells-1 Modulates the Inflammatory Response in Murine Sepsis","volume":"200","author":"Gibot","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/35074114","article-title":"TREM-1 amplifies inflammation and is a crucial mediator of septic shock","volume":"410","author":"Bouchon","year":"2001","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.4049\/jimmunol.166.10.6203","article-title":"Culture at High Density Improves the Ability of Human Macrophages to Control Mycobacterial Growth","volume":"166","author":"Boechat","year":"2001","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Weber, B., Schuster, S., Zysset, D., Rihs, S., Dickgreber, N., Schurch, C., Riether, C., Siegrist, M., Schneider, C., and Pawelski, H. (2014). TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003900"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/0022034512470691","article-title":"Elevated oral and systemic levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in periodontitis","volume":"92","author":"Bostanci","year":"2013","journal-title":"J. Dent. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1902\/jop.2017.170218","article-title":"Association of the Salivary Triggering Receptor Expressed on Myeloid Cells\/its Ligand Peptidoglycan Recognition Protein 1 Axis with Oral Inflammation in Kidney Disease","volume":"89","author":"Nylund","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1902\/jop.2013.130144","article-title":"Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) in Gingival Crevicular Fluid: Association with Clinical and Microbiologic Parameters","volume":"85","author":"Belibasakis","year":"2014","journal-title":"J. Periodontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1111\/jcpe.12008","article-title":"Increased gingival crevicular fluid levels of soluble triggering receptor expressed on myeloid cells (sTREM) -1 in severe periodontitis","volume":"39","author":"Bisson","year":"2012","journal-title":"J. Clin. Periodontol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"\u00d6zt\u00fcrk, V.\u00d6., Belibasakis, G.N., Emingil, G., and Bostanci, N. (2016). Impact of aging on TREM-1 responses in the periodontium: A cross-sectional study in an elderly population. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1778-6"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/cei.12397","article-title":"Expression and regulation of triggering receptor expressed on myeloid cells 1 in periodontal diseases","volume":"178","author":"Willi","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.molimm.2011.09.012","article-title":"Involvement of the TREM-1\/DAP12 pathway in the innate immune responses to Porphyromonas gingivalis","volume":"49","author":"Bostanci","year":"2011","journal-title":"Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/j.1574-695X.2012.00982.x","article-title":"Doxycycline inhibits TREM-1 induction by Porphyromonas gingivalis","volume":"66","author":"Bostanci","year":"2012","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","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":"ref_23","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1517\/13543776.2014.977865","article-title":"Triggering receptor expressed on myeloid cells receptor family modulators: A patent review","volume":"24","author":"Pelham","year":"2014","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"0797","DOI":"10.1126\/scitranslmed.aat0797","article-title":"A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans","volume":"10","author":"Dutzan","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1177\/154405910808700908","article-title":"A new inflammatory cytokine on the block: Re-thinking periodontal disease and the Th1\/Th2 paradigm in the context of Th17 cells and IL-17","volume":"87","author":"Gaffen","year":"2008","journal-title":"J. Dent. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/prd.12083","article-title":"Basic biology and role of interleukin-17 in immunity and inflammation","volume":"69","author":"Zenobia","year":"2015","journal-title":"Periodontol. 2000"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/j.1574-695X.2011.00863.x","article-title":"Induction of prostaglandin E 2 and interleukin-6 in gingival fibroblasts by oral biofilms","volume":"63","author":"Belibasakis","year":"2011","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/j.micinf.2008.08.007","article-title":"Porphyromonas gingivalis regulates the RANKL-OPG system in bone marrow stromal cells","volume":"10","author":"Reddi","year":"2008","journal-title":"Microbes Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1684\/ecn.2011.0274","article-title":"TREM-1 interaction with the LPS\/TLR4 receptor complex","volume":"22","author":"Arts","year":"2011","journal-title":"Eur. Cytokine Netw."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5558","DOI":"10.1038\/s41598-018-23808-2","article-title":"Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses","volume":"8","author":"Alflen","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/intimm\/dxl119","article-title":"Effects of TREM-1 activation in human neutrophils: Activation of signaling pathways, recruitment into lipid rafts and association with TLR4","volume":"19","author":"Fortin","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bostanci, N., Thurnheer, T., Aduse-Opoku, J., Curtis, M.A., Zinkernagel, A.S., and Belibasakis, G.N. (2013). Porphyromonas gingivalis Regulates TREM-1 in Human Polymorphonuclear Neutrophils via Its Gingipains. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075784"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/j.1600-051X.2005.00676.x","article-title":"The potential role of interleukin-17 in the immunopathology of periodontal disease","volume":"32","author":"Takahashi","year":"2005","journal-title":"J. Clin. Periodontol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1600-0765.2006.00946.x","article-title":"Differential expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin mRNA in periodontal diseases","volume":"42","author":"Bostanci","year":"2007","journal-title":"J. Periodontal Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/mi.2015.136","article-title":"Characterization of the human immune cell network at the gingival barrier","volume":"9","author":"Dutzan","year":"2016","journal-title":"Mucosal Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"229ra40","DOI":"10.1126\/scitranslmed.3007696","article-title":"Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss","volume":"6","author":"Moutsopoulos","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0002-9440(10)62961-6","article-title":"Blocking of Interleukin-17 during Reactivation of Experimental Arthritis Prevents Joint Inflammation and Bone Erosion by Decreasing RANKL and Interleukin-1","volume":"167","author":"Koenders","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"307ra155","DOI":"10.1126\/scitranslmed.aac5380","article-title":"DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates","volume":"7","author":"Shin","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ni.2260","article-title":"The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss","volume":"13","author":"Eskan","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/jcpe.12925","article-title":"Effects of Porphyromonas gingivalis LPS and LR12 peptide on TREM-1 expression by monocytes","volume":"45","author":"Dubar","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1038\/jid.2013.68","article-title":"TREM-1 as a potential therapeutic target in psoriasis","volume":"133","author":"Hyder","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.chom.2011.10.006","article-title":"Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement","volume":"10","author":"Hajishengallis","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1172\/JCI64181","article-title":"Transepithelial migration of neutrophils into the lung requires TREM-1","volume":"123","author":"Keck","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1177\/2380084419844937","article-title":"Regulation of PGLYRP1 and TREM-1 during Progression and Resolution of Gingival Inflammation","volume":"4","author":"Silbereisen","year":"2019","journal-title":"JDR Clin. Transl. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa011110","article-title":"Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent","volume":"345","author":"Keane","year":"2001","journal-title":"N. Engl. J. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1579\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:51Z","timestamp":1760189211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/10\/1579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,1]]},"references-count":45,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["jcm8101579"],"URL":"https:\/\/doi.org\/10.3390\/jcm8101579","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,1]]}}}