{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:36:00Z","timestamp":1793900160547,"version":"4.8.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periodontitis is a chronic inflammatory disease driven by immune dysregulation, in which neutrophils play a central but functionally heterogeneous role. The contributions of specific neutrophil subsets to disease pathogenesis remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single-cell RNA sequencing (scRNA-seq) and Mendelian randomization analysis to identify disease-associated immune cell subsets and gene regulatory mechanisms. Cell-type-specific interactions and pathway alterations were further analyzed to uncover potential pathogenic mediators. Key findings were validated using a murine ligature-induced periodontitis model, supplemented by targeted modulation of N4BP1 in primary human gingival epithelial cells and neutrophils.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a transcriptionally defined neutrophil subset that resembles previously reported low-density neutrophils, which we provisionally designate as LDN-1. This subset is characterized by aberrant interactions with epithelial cells primarily mediated by dysregulation of N4BP1. N4BP1 exhibited a dual, cell\u2212type\u2212specific role: its downregulation in epithelial cells impaired mucosal barrier integrity, leading to increased inflammatory tissue damage. In LDN\u22121, N4BP1 exhibited a context\u2212dependent regulatory function: it suppresses both pro-inflammatory CXCL1\/6-CXCR1\/2 signaling and anti-inflammatory ANXA1-FPR1\/FPR2 pathways. This duality suggests that N4BP1 may calibrate the balance between pro\u2212 and anti\u2212inflammatory signals during periodontitis progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify N4BP1 as a critical cell-type-specific molecular candidate that coordinates epithelial barrier function and neutrophil activity. Modulating N4BP1 or its downstream pathways may represent a potential precision therapeutic strategy for periodontitis and related inflammatory diseases, pending further interventional validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1830039","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:51:10Z","timestamp":1779943870000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual role of N4BP1 in neutrophil\u2013epithelial crosstalk in periodontitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuqiang","family":"Sun","sequence":"first","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZiHan","family":"Shen","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyu","family":"Zhen","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xu","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Lu","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Pan","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawei","family":"Mi","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Suzhou Hospital of Anhui Medical University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouzheng","family":"Ma","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wansu","family":"Sun","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Yu","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1600-0757.2011.00397.x","article-title":"Principles of periodontology","volume":"61","author":"Dentino","year":"2013","journal-title":"Periodontol 2000"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/JPER.19-0586","article-title":"Do patients with aggressive and chronic periodontitis exhibit specific differences in the subgingival microbial composition? 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