{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:17:42Z","timestamp":1791980262242,"version":"4.4.0"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,3,29]],"date-time":"2024-03-29T00:00:00Z","timestamp":1711670400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82301057"],"award-info":[{"award-number":["82301057"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["xzy012024106"],"award-info":[{"award-number":["xzy012024106"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["23YXYJ0151"],"award-info":[{"award-number":["23YXYJ0151"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023-YBSF-222"],"award-info":[{"award-number":["2023-YBSF-222"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundamental Research Funds for the Central Universities, Xi\u2019an Jiaotong University","award":["82301057"],"award-info":[{"award-number":["82301057"]}]},{"name":"Fundamental Research Funds for the Central Universities, Xi\u2019an Jiaotong University","award":["xzy012024106"],"award-info":[{"award-number":["xzy012024106"]}]},{"name":"Fundamental Research Funds for the Central Universities, Xi\u2019an Jiaotong University","award":["23YXYJ0151"],"award-info":[{"award-number":["23YXYJ0151"]}]},{"name":"Fundamental Research Funds for the Central Universities, Xi\u2019an Jiaotong University","award":["2023-YBSF-222"],"award-info":[{"award-number":["2023-YBSF-222"]}]},{"name":"Department of Science and Technology in Xi\u2019an, China","award":["82301057"],"award-info":[{"award-number":["82301057"]}]},{"name":"Department of Science and Technology in Xi\u2019an, China","award":["xzy012024106"],"award-info":[{"award-number":["xzy012024106"]}]},{"name":"Department of Science and Technology in Xi\u2019an, China","award":["23YXYJ0151"],"award-info":[{"award-number":["23YXYJ0151"]}]},{"name":"Department of Science and Technology in Xi\u2019an, China","award":["2023-YBSF-222"],"award-info":[{"award-number":["2023-YBSF-222"]}]},{"name":"Key Research and Development Program of Shaanxi, China","award":["82301057"],"award-info":[{"award-number":["82301057"]}]},{"name":"Key Research and Development Program of Shaanxi, China","award":["xzy012024106"],"award-info":[{"award-number":["xzy012024106"]}]},{"name":"Key Research and Development Program of Shaanxi, China","award":["23YXYJ0151"],"award-info":[{"award-number":["23YXYJ0151"]}]},{"name":"Key Research and Development Program of Shaanxi, China","award":["2023-YBSF-222"],"award-info":[{"award-number":["2023-YBSF-222"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Macrophages (M\u03c6s) play a crucial role in the homeostasis of the periapical immune micro-environment caused by bacterial infection. M\u03c6 efferocytosis has been demonstrated to promote the resolution of multiple infected diseases via accelerating M\u03c6 polarization into M2 type. However, the M\u03c6 efferocytosis\u2013apical periodontitis (AP) relationship has not been elucidated yet. This study aimed to explore the role of M\u03c6 efferocytosis in the pathogenesis of AP. Clinical specimens were collected to determine the involvement of M\u03c6 efferocytosis in the periapical region via immunohistochemical and immunofluorescence staining. For a further understanding of the moderator effect of M\u03c6 efferocytosis in the pathogenesis of AP, both an in vitro AP model and in vivo AP model were treated with ARA290, a M\u03c6 efferocytosis agonist. Histological staining, micro-ct, flow cytometry, RT-PCR and Western blot analysis were performed to detect the inflammatory status, alveolar bone loss and related markers in AP models. The data showed that M\u03c6 efferocytosis is observed in the periapical tissues and enhancing the M\u03c6 efferocytosis ability could effectively promote AP resolution via facilitating M2 M\u03c6 polarization. Collectively, our study demonstrates the functional importance of M\u03c6 efferocytosis in AP pathology and highlights that accelerating M\u03c6 efferocytosis via ARA290 could serve as an adjuvant therapeutic strategy for AP.<\/jats:p>","DOI":"10.3390\/ijms25073854","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T13:42:30Z","timestamp":1711892550000},"page":"3854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis"],"prefix":"10.3390","volume":"25","author":[{"given":"Xiaoyue","family":"Guan","sequence":"first","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlan","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial 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Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingfei","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7846-9170","authenticated-orcid":false,"given":"Abdelrahman","family":"Seyam","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, 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Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiezhou","family":"Hou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"},{"name":"Department of Cariology and Endodontics, College of Stomatology, Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.tripleo.2009.01.042","article-title":"Bacteria in the apical root canal of teeth with primary apical periodontitis","volume":"107","author":"Siqueira","year":"2009","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/iej.13760","article-title":"Expression of PINK1 and Parkin in human apical periodontitis","volume":"55","author":"Liu","year":"2022","journal-title":"Int. Endod. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1111\/iej.13736","article-title":"Outcomes of primary root canal therapy: An updated systematic review of longitudinal clinical studies published between 2003 and 2020","volume":"55","author":"Burns","year":"2022","journal-title":"Int. Endod. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1038\/s41598-021-82167-7","article-title":"Inhibition of the CXCL9-CXCR3 axis suppresses the progression of experimental apical periodontitis by blocking macrophage migration and activation","volume":"11","author":"Hasegawa","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"112808","DOI":"10.1016\/j.celrep.2023.112808","article-title":"Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling","volume":"42","author":"Bhattacharya","year":"2023","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e131355","DOI":"10.1172\/jci.insight.131355","article-title":"STAT6\/Arg1 promotes microglia\/macrophage efferocytosis and inflammation resolution in stroke mice","volume":"4","author":"Cai","year":"2019","journal-title":"JCI Insight"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/cbf.3780","article-title":"Macrophage efferocytosis in health and disease","volume":"41","author":"Razi","year":"2023","journal-title":"Cell Biochem. Funct."},{"key":"ref_8","first-page":"183","article-title":"Engineered neutrophil apoptotic bodies ameliorate myocardial infarction by promoting macrophage efferocytosis and inflammation resolution","volume":"9","author":"Bao","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/imr.13214","article-title":"The role of efferocytosis-fueled macrophage metabolism in the resolution of inflammation","volume":"319","author":"Schilperoort","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1016\/j.cmet.2021.10.015","article-title":"Efferocytosis induces macrophage proliferation to help resolve tissue injury","volume":"33","author":"Gerlach","year":"2021","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/bs.ircmb.2021.02.002","article-title":"Tyro3, Axl, Mertk receptor-mediated efferocytosis and immune regulation in the tumor environment","volume":"361","author":"Zhou","year":"2021","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12943-019-1022-2","article-title":"Targeting Tyro3, Axl and MerTK (TAM receptors): Implications for macrophages in the tumor microenvironment","volume":"18","author":"Myers","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2169\/internalmedicine.3302-19","article-title":"An ERG Gene Analysis in Two Cases with Metastatic Castration-resistant Prostate Cancer in Which Abiraterone Demonstrated Long-term Efficacy","volume":"59","author":"Yoshizawa","year":"2020","journal-title":"Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e83069","DOI":"10.7554\/eLife.83069","article-title":"Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis","volume":"12","author":"Yao","year":"2023","journal-title":"Elife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"231","DOI":"10.7150\/thno.78878","article-title":"SIRT6-regulated macrophage efferocytosis epigenetically controls inflammation resolution of diabetic periodontitis","volume":"13","author":"Li","year":"2023","journal-title":"Theranostics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41590-018-0249-1","article-title":"DEL-1 promotes macrophage efferocytosis and clearance of inflammation","volume":"20","author":"Kourtzelis","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1161\/CIRCRESAHA.123.323223","article-title":"CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis","volume":"134","author":"Lv","year":"2024","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/art.42412","article-title":"Impaired Efferocytosis by Synovial Macrophages in Patients with Knee Osteoarthritis","volume":"75","author":"Blackler","year":"2023","journal-title":"Arthritis Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2100829","DOI":"10.1183\/13993003.00829-2021","article-title":"Acute respiratory distress syndrome is associated with impaired alveolar macrophage efferocytosis","volume":"58","author":"Mahida","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.1016\/j.neuron.2022.10.015","article-title":"Microglial efferocytosis: Diving into the Alzheimer\u2019s disease gene pool","volume":"110","author":"Garretti","year":"2022","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.immuni.2023.06.026","article-title":"Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis","volume":"56","author":"Kiss","year":"2023","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1042\/bj3570593","article-title":"Nitric oxide synthases: Structure, function and inhibition","volume":"357","author":"Alderton","year":"2001","journal-title":"Biochem. J."},{"key":"ref_23","first-page":"146","article-title":"Cryptosporidiosis\u2014Causative agent, epidemiology, clinical picture and diagnosis","volume":"111","author":"Muller","year":"1986","journal-title":"Dtsch. Med. Wochenschr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1111\/jcmm.13608","article-title":"Non-erythropoietic erythropoietin-derived peptide protects mice from systemic lupus erythematosus","volume":"22","author":"Huang","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"896601","DOI":"10.3389\/fphar.2022.896601","article-title":"Nonerythropoietic Erythropoietin Mimetic Peptide ARA290 Ameliorates Chronic Stress-Induced Depression-Like Behavior and Inflammation in Mice","volume":"13","author":"Xu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_26","first-page":"11","article-title":"MFG-E8 promotes tendon-bone healing by regualting macrophage efferocytosis and M2 polarization after anterior cruciate ligament reconstruction","volume":"34","author":"Geng","year":"2022","journal-title":"J. Orthop. Transl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/s12276-022-00840-x","article-title":"BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity","volume":"54","author":"Bae","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1016\/j.jcmgh.2022.01.002","article-title":"Macrophage COX2 Mediates Efferocytosis, Resolution Reprogramming, and Intestinal Epithelial Repair","volume":"13","author":"Meriwether","year":"2022","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"738586","DOI":"10.3389\/fimmu.2021.738586","article-title":"VISTA Blockade Aggravates Bone Loss in Experimental Murine Apical Periodontitis","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jim.2013.11.006","article-title":"Reduced PMA enhances the responsiveness of transfected THP-1 macrophages to polarizing stimuli","volume":"402","author":"Wittig","year":"2014","journal-title":"J. Immunol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Huang, Y., Tian, C., Li, Q., and Xu, Q. (2019). TET1 Knockdown Inhibits Porphyromonas gingivalis LPS\/IFN-\u03b3-Induced M1 Macrophage Polarization through the NF-\u03baB Pathway in THP-1 Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20082023"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"110192","DOI":"10.1016\/j.intimp.2023.110192","article-title":"Glycolytic reprogramming controls periodontitis-associated macrophage pyroptosis via AMPK\/SIRT1\/NF-\u03baB signaling pathway","volume":"119","author":"He","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.1111\/febs.15135","article-title":"PLAG enhances macrophage mobility for efferocytosis of apoptotic neutrophils via membrane redistribution of P2Y2","volume":"286","author":"Kim","year":"2019","journal-title":"FEBS J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/JPER.21-0474","article-title":"Gremlin aggravates periodontitis via activation of the nuclear factor-kappa B signaling pathway","volume":"93","author":"Guan","year":"2022","journal-title":"J. Periodontol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3854\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:21:10Z","timestamp":1760106070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/7\/3854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,29]]},"references-count":34,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25073854"],"URL":"https:\/\/doi.org\/10.3390\/ijms25073854","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,29]]}}}