{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T09:55:33Z","timestamp":1791453333364,"version":"4.3.3"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,2,1]],"date-time":"2013-02-01T00:00:00Z","timestamp":1359676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Porphyromonas gingivalis is a primary etiological agent of chronic periodontal disease, an infection-driven chronic inflammatory disease that leads to the resorption of tooth-supporting alveolar bone. We previously reported that TLR2 is required for P. gingivalis\u2013induced alveolar bone loss in vivo, and our in vitro work implicated TNF as a key downstream mediator. In this study, we show that TNF-deficient (Tnf\u2212\/\u2212) mice are resistant to alveolar bone loss following oral infection with P. gingivalis, and thus establish a central role for TNF in experimental periodontal disease. Using bone marrow\u2013derived macrophages (BMDM) from wild-type and gene-specific knockout mice, we demonstrate that the initial inflammatory response to P. gingivalis in naive macrophages is MyD88 dependent and requires cooperative signaling of TLR2 and TLR4. The ability of P. gingivalis to activate cells via TLR2 or TLR4 was confirmed in TLR2- or TLR4-transformed human embryonic kidney cells. Additional studies using bacterial mutants demonstrated a role for fimbriae in the modulation of TLR-mediated activation of NF-\u03baB. Whereas both TLR2 and TLR4 contributed to TNF production in naive macrophages, P. gingivalis preferentially exploited TLR2 in endotoxin-tolerant BMDM to trigger excessive TNF production. We found that TNF induced surface TLR2 expression and augmented TLR-induced cytokine production in P. gingivalis\u2013stimulated BMDM, establishing a previously unidentified TNF-dependent feedback loop. Adoptive transfer of TLR2-expressing macrophages to TLR2-deficient mice restored the ability of P. gingivalis to induce alveolar bone loss in vivo. Collectively, our results identify a TLR2- and TNF-dependent macrophage-specific mechanism underlying pathogen-induced inflammatory bone loss in vivo.<\/jats:p>","DOI":"10.4049\/jimmunol.1202511","type":"journal-article","created":{"date-parts":[[2012,12,22]],"date-time":"2012-12-22T02:13:02Z","timestamp":1356142382000},"page":"1148-1157","source":"Crossref","is-referenced-by-count":133,"title":["Macrophage-Specific TLR2 Signaling Mediates Pathogen-Induced TNF-Dependent Inflammatory Oral Bone Loss"],"prefix":"10.1093","volume":"190","author":[{"given":"George","family":"Papadopoulos","sequence":"first","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen O","family":"Weinberg","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Massari","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Frank C","family":"Gibson","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee M","family":"Wetzler","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise F","family":"Morgan","sequence":"additional","affiliation":[{"name":"Orthopedic and Developmental Biomechanics Laboratory, Department of Mechanical Engineering, College of Engineering, Boston University , Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline A","family":"Genco","sequence":"additional","affiliation":[{"name":"Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine , Boston, MA 02118"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,2,1]]},"reference":[{"key":"2025032406292573900_r1","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","article-title":"Periodontal diseases","volume":"366","author":"Pihlstrom","year":"2005","journal-title":"Lancet"},{"key":"2025032406292573900_r2","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1177\/0022034510377793","article-title":"Accuracy of NHANES periodontal examination protocols","volume":"89","author":"Eke","year":"2010","journal-title":"J. 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