{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:11:16Z","timestamp":1783923076304,"version":"3.55.0"},"reference-count":201,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"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. Immunol."],"abstract":"<jats:p>Periodontitis is a chronic immunoinflammatory disease characterized by site-specific destruction of the tooth-supporting tissues and marked heterogeneity in disease susceptibility, progression, and response to therapy. While dysbiotic subgingival biofilms initiate disease, microbial burden alone cannot explain the persistence of inflammation or the limited predictability of regenerative outcomes. Increasing evidence implicates innate immune dysregulation, particularly Toll-like receptor (TLR) signaling, as a central determinant of periodontal disease behavior. This narrative review synthesizes current evidence on TLR signaling in periodontal tissues, emphasizing the concept that chronic periodontitis is sustained by biased downstream signaling integration rather than uniform receptor overactivation. We discuss how persistent dominance of pro-inflammatory, MyD88-dependent pathways, coupled with insufficient engagement of regulatory and resolution-associated programs, promotes inflammatory persistence, osteoimmune imbalance, and functional impairment of periodontal stromal and stem\/progenitor cells. Cell-type\u2013specific responses to TLR activation, genetic modulation of signaling thresholds, and reciprocal interactions between innate immunity and dysbiosis are examined as key contributors to disease heterogeneity. We further explore the implications of biased TLR signaling for periodontal regeneration, proposing that regenerative failure reflects an unfavorable inflammatory signaling milieu rather than depletion of regenerative cell populations. Finally, emerging experimental strategies for interrogating and modulating TLR signaling networks\u2014including localized immune modulation and targeted protein degradation approaches\u2014are discussed as mechanistic research tools rather than immediate therapeutic solutions. By reframing periodontitis as a disorder of maladaptive innate immune signaling integration, this review provides a unifying conceptual framework linking dysbiosis, host-response heterogeneity, and impaired regeneration, and defines priorities for future mechanistic and translational research.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1852272","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T05:35:23Z","timestamp":1783920923000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond receptor activation: biased toll-like receptor signaling in periodontal inflammation and regeneration"],"prefix":"10.3389","volume":"17","author":[{"given":"Mohamed","family":"Mekhemar","sequence":"first","affiliation":[{"name":"Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Christian-Albrecht\u2019s University","place":["Kiel, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma E. A.","family":"Hassanein","sequence":"additional","affiliation":[{"name":"King Salman International University","place":["El Tor, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Abou-Bakr","sequence":"additional","affiliation":[{"name":"Galala University","place":["Suez, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/prd.12568","article-title":"The economic and societal impact of periodontal and peri-implant diseases","volume":"98","author":"Saleh","year":"2025","journal-title":"Periodontology 2000"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/prd.12371","article-title":"Polymicrobial communities in periodontal disease: their quasi-organismal nature and dialogue with the host","volume":"86","author":"Hajishengallis","year":"2021","journal-title":"Periodontol 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