{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:16:10Z","timestamp":1791317770689,"version":"4.3.1"},"reference-count":42,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T00:00:00Z","timestamp":1690588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences: SC INBRE University of South Carolina\/NIGMS","award":["2P20GM103499-20"],"award-info":[{"award-number":["2P20GM103499-20"]}]},{"name":"National Institute of General Medical Sciences: SC INBRE University of South Carolina\/NIGMS","award":["R01DE030313"],"award-info":[{"award-number":["R01DE030313"]}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["2P20GM103499-20"],"award-info":[{"award-number":["2P20GM103499-20"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE030313"],"award-info":[{"award-number":["R01DE030313"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MUSC College of Dental Medicine Scholars Grant","award":["2P20GM103499-20"],"award-info":[{"award-number":["2P20GM103499-20"]}]},{"name":"MUSC College of Dental Medicine Scholars Grant","award":["R01DE030313"],"award-info":[{"award-number":["R01DE030313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Periodontal disease (PD) is a chronic inflammatory disorder characterized by the destruction of connective tissue, tooth loss, and systemic infections. Clinically, treatment of PD includes control of the etiologic factors via several modalities: initial therapy including scaling and root planing (SRP), corrective phase of surgical treatment, both with and without adjunct antimicrobial\/pharmacological agents, followed by a maintenance\/supportive periodontal therapy phase. Each treatment phase aims to control oral biofilm by addressing risk factors and etiology. Monotherapy of systemic antibiotics is insufficient compared to their use as an adjunct to SRP. The critical issue of systemic antimicrobial usage includes adverse patient outcomes and increased bacterial resistance. Therefore, alternative adjuncts to periodontal therapy have been sought. Statins are widely prescribed for the treatment of hypercholesterolemia and cardiovascular disease. Statins have demonstrated anti-inflammatory properties and immunomodulatory effects, and a few retrospective studies showed that statin patients exhibit fewer signs of periodontal inflammation than subjects without the medication. Despite the available clinical studies on the local administration of statins for PD, no studies have reported the macrophage polarization response. We have developed a gingival fibroblast\u2013macrophage co-culture model to track macrophage response when exposed to a battery of microenvironmental cues mimicking macrophage polarization\/depolarization observed in vivo. Using our model, we demonstrate that simvastatin suppresses macrophage inflammatory response and upregulates tissue homeostasis and M2 macrophage markers. Our findings support the usage of statins to mitigate periodontal inflammation as a valid strategy.<\/jats:p>","DOI":"10.3390\/cells12151961","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:39:32Z","timestamp":1690767572000},"page":"1961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Statins Modulate Microenvironmental Cues Driving Macrophage Polarization in Simulated Periodontal Inflammation"],"prefix":"10.3390","volume":"12","author":[{"given":"Waleed","family":"Alkakhan","sequence":"first","affiliation":[{"name":"Department of Oral Health Sciences, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"},{"name":"Division of Periodontics, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Farrar","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Sikora","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8591-4140","authenticated-orcid":false,"given":"Pinar","family":"Emecen-Huja","sequence":"additional","affiliation":[{"name":"Division of Periodontics, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4617-5055","authenticated-orcid":false,"given":"Sarandeep S.","family":"Huja","sequence":"additional","affiliation":[{"name":"Division of Orthodontics, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3487-7217","authenticated-orcid":false,"given":"\u00d6zlem","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9568-7666","authenticated-orcid":false,"given":"Subramanya N.","family":"Pandruvada","sequence":"additional","affiliation":[{"name":"Department of Oral Health Sciences, James B. Edwards College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/prd.12135","article-title":"Aging, Inflammation, Immunity and Periodontal Disease","volume":"72","author":"Ebersole","year":"2016","journal-title":"Periodontol. 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1034\/j.1600-0757.2002.03006.x","article-title":"In or Out: The Invasiveness of Oral Bacteria","volume":"30","author":"Lamont","year":"2002","journal-title":"Periodontol. 2000"},{"key":"ref_3","first-page":"7","article-title":"In Situ Intraepithelial Localizations of Opportunistic Pathogens, Porphyromonas Gingivalis and Filifactor Alocis, in Human Gingiva","volume":"1","author":"Lee","year":"2020","journal-title":"Curr. Res. Microb. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1177\/0022034520973012","article-title":"Key Elements of Gingival Epithelial Homeostasis Upon Bacterial Interaction","volume":"100","author":"Lee","year":"2020","journal-title":"J. Dent. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1080\/21505594.2018.1454171","article-title":"Porphyromonas Gingivalis Traffics into Endoplasmic Reticulum-Rich-Autophagosomes for Successful Survival in Human Gingival Epithelial Cells","volume":"9","author":"Lee","year":"2018","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"30385","DOI":"10.3402\/jom.v8.30385","article-title":"Modulation of Inflammasome Activity by Porphyromonas Gingivalis in Periodontitis and Associated Systemic Diseases","volume":"8","author":"Ingar","year":"2016","journal-title":"J. Oral. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1046\/j.0906-6713.2003.03203.x","article-title":"Microorganisms as Risk Indicators for Periodontal Disease","volume":"32","author":"Ezzo","year":"2003","journal-title":"Periodontol. 2000"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36s","DOI":"10.14219\/jada.archive.2009.0356","article-title":"The Biology, Prevention, Diagnosis and Treatment of Periodontal Diseases: Scientific Advances in the United States","volume":"140","author":"Armitage","year":"2009","journal-title":"J. Am. Dent. Assoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ni.2419","article-title":"Gene-Expression Profiles and Transcriptional Regulatory Pathways That Underlie the Identity and Diversity of Mouse Tissue Macrophages","volume":"13","author":"Gautier","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1038\/nri3088","article-title":"Transcriptional Regulation of Macrophage Polarization: Enabling Diversity with Identity","volume":"11","author":"Lawrence","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/odi.12983","article-title":"Macrophage Polarization in Human Gingival Tissue in Response to Periodontal Disease","volume":"25","author":"Zhou","year":"2019","journal-title":"Oral Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The Chemokine System in Diverse Forms of Macrophage Activation and Polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33638","DOI":"10.1038\/srep33638","article-title":"In Situ Anabolic Activity of Periodontal Pathogens Porphyromonas Gingivalis and Filifactor Alocis in Chronic Periodontitis","volume":"6","author":"Spooner","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/j.1875-595X.2002.tb00882.x","article-title":"Mouthrinses and Periodontal Disease","volume":"52","author":"Reich","year":"2002","journal-title":"Int. Dent. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1111\/j.0303-6979.2004.00490.x","article-title":"Efficacy of Antibiotics to Strains of Periodontopathogenic Bacteria within a Single Species Biofilm\u2014An in Vitro Study","volume":"31","author":"Eick","year":"2004","journal-title":"J. Clin. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1600-051X.2008.01260.x","article-title":"Antimicrobial Therapy in Periodontitis: The Use of Systemic Antimicrobials against the Subgingival Biofilm","volume":"35","author":"Herrera","year":"2008","journal-title":"J. Clin. Periodontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1902\/jop.2016.150698","article-title":"Synergistic Approach Using Platelet-Rich Fibrin and 1% Alendronate for Intrabony Defect Treatment in Chronic Periodontitis: A Randomized Clinical Trial","volume":"87","author":"Kanoriya","year":"2016","journal-title":"J. Periodontol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Elabdeen, H.R.Z., Mustafa, M., Szklenar, M., R\u00fchl, R., Ali, R., and Bolstad, A.I. (2013). Ratio of Pro-Resolving and Pro-Inflammatory Lipid Mediator Precursors as Potential Markers for Aggressive Periodontitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070838"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1177\/0022034514541125","article-title":"Docosahexaenoic Acid and Periodontitis in Adults: A Randomized Controlled Trial","volume":"93","author":"Naqvi","year":"2014","journal-title":"J. Dent. Res."},{"key":"ref_20","first-page":"S19","article-title":"Shifting the Paradigm from Inhibitors of Inflammation to Resolvers of Inflammation in Periodontitis","volume":"91","year":"2020","journal-title":"J. Periodontol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Foey, A.D., and Crean, S. (2013). Macrophage Subset Sensitivity to Endotoxin Tolerisation by Porphyromonas Gingivalis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067955"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.mehy.2005.03.012","article-title":"Cholesterol Synthesis Is the Trigger and Isoprenoid Dependent Interleukin-6 Mediated Inflammation Is the Common Causative Factor and Therapeutic Target for Atherosclerotic Vascular Disease and Age-Related Disorders Including Osteoporosis and Type 2 Diabetes","volume":"65","author":"Omoigui","year":"2005","journal-title":"Med. Hypotheses"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/j.1600-0765.2004.00731.x","article-title":"Periodontal Disease and C-Reactive Protein-Associated Cardiovascular Risk","volume":"39","author":"Ready","year":"2004","journal-title":"J. Periodontal. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lindy, O., Suomalainen, K., M\u00e4kel\u00e4, M., and Lindy, S. (2008). Statin Use Is Associated with Fewer Periodontal Lesions: A Retrospective Study. BMC Oral Health, 8.","DOI":"10.1186\/1472-6831-8-16"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1096\/fba.2018-00018","article-title":"Inhibition of Osteoclastogenesis by Opsonized Porphyromonas Gingivalis","volume":"1","author":"Pandruvada","year":"2019","journal-title":"FASEB BioAdvances"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"112721","DOI":"10.1016\/j.jim.2019.112721","article-title":"Standardized Protocols for Differentiation of Thp-1 Cells to Macrophages with Distinct M(Ifngamma+Lps), M(Il-4) and M(Il-10) Phenotypes","volume":"478","author":"Baxter","year":"2020","journal-title":"J. Immunol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/JPER.19-0137","article-title":"Cd73-Dependent Adenosine Dampens Interleukin-1\u03b2-Induced Cxcl8 Production in Gingival Fibroblasts: Association with Heme Oxygenase-1 and Adenosine Monophosphate-Activated Protein Kinase","volume":"91","author":"Pedram","year":"2020","journal-title":"J. Periodontol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cellimm.2013.01.010","article-title":"Polarization Profiles of Human M-Csf-Generated Macrophages and Comparison of M1-Markers in Classically Activated Macrophages from Gm-Csf and M-Csf Origin","volume":"281","author":"Jaguin","year":"2013","journal-title":"Cell. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.tiv.2017.08.011","article-title":"Development of an in Vitro Co-Culture Model to Mimic the Human Intestine in Healthy and Diseased State","volume":"45","author":"Gioria","year":"2017","journal-title":"Toxicol. Vitr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14246","DOI":"10.1038\/srep14246","article-title":"Discovery of Small Molecule Inhibitors of Myd88-Dependent Signaling Pathways Using a Computational Screen","volume":"5","author":"Olson","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1773122","DOI":"10.1080\/20002297.2020.1773122","article-title":"A Review of Co-Culture Models to Study the Oral Microenvironment and Disease","volume":"12","author":"Mountcastle","year":"2020","journal-title":"J. Oral Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3389\/fimmu.2014.00514","article-title":"From Monocytes to M1\/M2 Macrophages: Phenotypical vs. Functional Differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11516","DOI":"10.1038\/s41598-017-11771-3","article-title":"Oral Fibroblasts Modulate the Macrophage Response to Bacterial Challenge","volume":"7","author":"Nashef","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ftw011","DOI":"10.1093\/femspd\/ftw011","article-title":"Macrophage Polarization in Response to Oral Commensals and Pathogens","volume":"74","author":"Huang","year":"2016","journal-title":"Pathog. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.4049\/jimmunol.1400853","article-title":"Macrophage Depletion Abates Porphyromonas gingivalis\u2013Induced Alveolar Bone Resorption in Mice","volume":"193","author":"Lam","year":"2014","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4190","DOI":"10.1128\/IAI.02325-14","article-title":"Porphyromonas gingivalis Lipopolysaccharide Weakly Activates M1 and M2 Polarized Mouse Macrophages but Induces Inflammatory Cytokines","volume":"82","author":"Holden","year":"2014","journal-title":"Infect. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"705","DOI":"10.3389\/fimmu.2019.00705","article-title":"Nf-\u039ab Signaling in Macrophages: Dynamics, Crosstalk, and Signal Integration","volume":"10","author":"Dorrington","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1056\/NEJM200106283442601","article-title":"Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events","volume":"344","author":"Ridker","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev.pharmtox.45.120403.095748","article-title":"Pleiotropic Effects of Statins","volume":"45","author":"Liao","year":"2005","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3390\/immuno2020021","article-title":"The Immunomodulatory Effects of Statins on Macrophages","volume":"2","author":"Sheridan","year":"2022","journal-title":"Immuno"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Jin, Y., Tachibana, I., Takeda, Y., He, P., Kang, S., Suzuki, M., Kuhara, H., Tetsumoto, S., Tsujino, K., and Minami, T. (2013). Statins Decrease Lung Inflammation in Mice by Upregulating Tetraspanin Cd9 in Macrophages. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073706"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1002\/eji.200838189","article-title":"The Ifn-Gamma-Induced Transcriptional Program of the Ciita Gene Is Inhibited by Statins","volume":"38","author":"Lee","year":"2008","journal-title":"Eur. J. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/15\/1961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:22:00Z","timestamp":1760127720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/15\/1961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,29]]},"references-count":42,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["cells12151961"],"URL":"https:\/\/doi.org\/10.3390\/cells12151961","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,29]]}}}