{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:16:59Z","timestamp":1790101019144,"version":"4.0.1"},"reference-count":70,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"HHS | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE029034"],"award-info":[{"award-number":["R01DE029034"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,9,3]]},"abstract":"<jats:p>Many chronic inflammatory diseases are attributed to disturbances in host\u2013microbe interactions, which drive immune-mediated tissue damage. Depending on the anatomic setting, a chronic inflammatory disease can exert unique local and systemic influences, which provide an exceptional opportunity for understanding disease mechanism and testing therapeutic interventions. The oral cavity is an easily accessible environment that allows for protective interventions aiming at modulating the immune response to control disease processes driven by a breakdown of host\u2013microbe homeostasis. Periodontal disease (PD) is a prevalent condition in which quantitative and qualitative changes of the oral microbiota (dysbiosis) trigger nonresolving chronic inflammation, progressive bone loss, and ultimately tooth loss. Here, we demonstrate the therapeutic benefit of local sustained delivery of the myeloid-recruiting chemokine (C-C motif) ligand 2 (CCL2) in murine ligature-induced PD using clinically relevant models as a preventive, interventional, or reparative therapy. Local delivery of CCL2 into the periodontium inhibited bone loss and accelerated bone gain that could be ascribed to reduced osteoclasts numbers. CCL2 treatment up-regulated M2-macrophage and downregulated proinflammatory and pro-osteoclastic markers. Furthermore, single-cell ribonucleic acid (RNA) sequencing indicated that CCL2 therapy reversed disease-associated transcriptomic profiles of murine gingival macrophages via inhibiting the triggering receptor expressed on myeloid cells-1 (TREM-1) signaling in classically activated macrophages and inducing protein kinase A (PKA) signaling in infiltrating macrophages. Finally, 16S ribosomal ribonucleic acid (rRNA) sequencing showed mitigation of microbial dysbiosis in the periodontium that correlated with a reduction in microbial load in CCL2-treated mice. This study reveals a novel protective effect of CCL2 local delivery in PD as a model for chronic inflammatory diseases caused by a disturbance in host\u2013microbe homeostasis.<\/jats:p>","DOI":"10.1073\/pnas.2400528121","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T15:05:06Z","timestamp":1724684706000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Therapeutic delivery of CCL2 modulates immune response and restores host\u2013microbe homeostasis"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2122-4105","authenticated-orcid":false,"given":"Mostafa","family":"Shehabeldin","sequence":"first","affiliation":[{"name":"Center for Craniofacial Regeneration, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"},{"name":"Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"},{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6200-4141","authenticated-orcid":false,"given":"Jin","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Regeneration, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1500-9222","authenticated-orcid":false,"given":"Yejin","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Chong","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Regeneration, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Tabib","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"},{"name":"University at Buffalo Microbiome Center, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Smardz","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"},{"name":"University at Buffalo Microbiome Center, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8511-2041","authenticated-orcid":false,"given":"Sarah L.","family":"Gaffen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia I.","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"},{"name":"University at Buffalo Microbiome Center, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, NY 14214"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9398-5034","authenticated-orcid":false,"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7000-3931","authenticated-orcid":false,"given":"Steven R.","family":"Little","sequence":"additional","affiliation":[{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219"},{"name":"Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Sfeir","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Regeneration, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"},{"name":"Department of Periodontics and Preventive Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"},{"name":"Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3785"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.09.001"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0765.2001.360205.x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2016.160081"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/odi.12983"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxy054"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-chembioeng-073009-100847"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/0194599817730304"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202202720"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302829110"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034518805984"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2376"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2013.05.002"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24554"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30602"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13151"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010128"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160459"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2015.140520"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034514552491"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.12241"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aau3333"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.048"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.13435"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01381.x"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2017-210741"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2466-14-112"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1159\/000023825"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091574"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.042671"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302821"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034518777973"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96832"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117606"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041650321"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1461"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.2.275"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600859"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402166"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.367"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1563\/aaid-joi-D-17-00157"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0249-1"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00037.2016"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.07.141"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3607"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142883"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1159\/000495276"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28549"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00461-16"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.02.043"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.12008"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1177\/0022034512470691"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12397"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8101579"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-09-010116"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01209-07"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat0797"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2260"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601650"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00785"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00242.2012"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1111\/prd.12296"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.10.6514-6522.2005"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31827802b5"},{"key":"e_1_3_4_66_2","first-page":"53736","article-title":"Isolation, characterization and functional examination of the gingival immune cell network","volume":"108","author":"Dutzan N.","year":"2016","unstructured":"N. Dutzan , Isolation, characterization and functional examination of the gingival immune cell network. J. Vis. Exp., 108, 53736 (2016).","journal-title":"J. Vis. Exp."},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/ismej.2012.174"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008230"},{"key":"e_1_3_4_69_2","unstructured":"M. Shehabeldin T. Tabib R. Lafyatis C. Sfeir Single-cell RNA sequencing of murine gingival immune cells following ligature periodontitis induction. Gene Expression Omnibus (GEO). https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE274721. Deposited 13 August 2024."},{"key":"e_1_3_4_70_2","unstructured":"M. Shehabeldin L. Li P. Diaz C. Sfeir 16S rRNA sequence of periodontal biolfilm from balb\/c mice with ligature-induced periodontitis. NCBI Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/1139767. Deposited 24 July 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2400528121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T15:05:26Z","timestamp":1724684726000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2400528121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,26]]},"references-count":70,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2024,9,3]]}},"alternative-id":["10.1073\/pnas.2400528121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2400528121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,26]]},"assertion":[{"value":"2024-01-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2400528121"}}