Advertisement

The Potential Immunomodulatory Roles of Semaphorin 4D in Human Periapical Lesions

  • Author Footnotes
    ∗ Yanglin Zeng and Liu Wang contributed equally to this article.
    Yanglin Zeng
    Footnotes
    ∗ Yanglin Zeng and Liu Wang contributed equally to this article.
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Author Footnotes
    ∗ Yanglin Zeng and Liu Wang contributed equally to this article.
    Liu Wang
    Footnotes
    ∗ Yanglin Zeng and Liu Wang contributed equally to this article.
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Liu Liu
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Mudan Wang
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Lixia Yan
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Ling Ye
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Dongzhe Song
    Correspondence
    Correspondence should be addressed to: Dongzhe Song.
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Dingming Huang
    Correspondence
    Correspondence should be addressed to: Dingming Huang.
    Affiliations
    State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China

    Department of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
    Search for articles by this author
  • Author Footnotes
    ∗ Yanglin Zeng and Liu Wang contributed equally to this article.
Published:October 14, 2022DOI:https://doi.org/10.1016/j.joen.2022.10.003

      Abstract

      Introduction

      Semaphorin 4D (SEMA4D) is an important immunoregulator in the development of inflammatory diseases. Currently, the role of SEMA4D in human apical periodontitis remains unclear. This study aims to investigate the expression of SEMA4D and its potential immunomodulatory roles in apical periodontitis.

      Methods

      A total of 31 periapical tissues and 6 healthy gingival tissues were used in this experiment. Hematoxylin-eosin (H&E) staining, immunohistochemical staining, and multiplex immunofluorescence staining were performed for histologic examination and immunochemical analysis. For data processing, the number of SEMA4D+, CD4+, CD8+, and CD20+ cells was analyzed by QuPath. In addition, the colocalization of SEMA4D with CD4, CD8, and CD20 was detected.

      Results

      Radicular cysts (n =18) and periapical granulomas (n =13) were identified by histologic evaluation. The number of SEMA4D+ cells in PGs was significantly greater than that in RCs (p<0.05). T-cell and B-cell infiltration did not differ significantly between RCs and PGs. An increased number of CD20+ cells was observed in both types of apical periodontitis compared to CD8+ cells and CD4+ cells. Additionally, the presence of SEMA4D/CD4 and SEMA4D/CD20 double-positive cells was also markedly higher in PGs than in RCs.

      Conclusion

      The expression of SEMA4D and related immune cells showed different characteristics between radicular cysts and periapical granulomas. The disparate expression patterns indicated the possible different pathologic states of the two types of periapical lesions. This study provides a new perspective on the description of the comprehensive microenvironment of periapical lesions.

      Key Word

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Endodontics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      Reference

      1. Louis H.B, Kenneth M.H. Cohen's Pathways of the Pulp[M]. 12th ed. Missouri: Elsevier Inc, 2021.

        • Liapatas S.
        • Nakou M.
        • Rontogianni D.
        Inflammatory infiltrate of chronic periradicular lesions: an immunohistochemical study.
        Int Endod J. 2003; 36: 464-471
      2. Ricucci D, Siqueira JF Jr. Endodontology: An Integrated Biology and Clinical View[M]. United Kingdom: Quintessence Publishing Co. Ltd, 2013.

        • Wang L.
        • Li X.
        • Song Y.
        • Song D.
        • Huang D.
        The emerging roles of semaphorin4D/CD100 in immunological diseases.
        Biochem Soc Trans. 2020; 48: 2875-2890
        • Yoshida Y.
        • Ogata A.
        • Kang S.
        • Ebina K.
        • Shi K.
        • Nojima S.
        • et al.
        Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications.
        Arthritis Rheumatol. 2015; 67: 1481-1490
        • Ke Y.
        • Dang E.
        • Shen S.
        • Zhang T.
        • Qiao H.
        • Chang Y.
        • et al.
        Semaphorin4D Drives CD8(+) T-Cell Lesional Trafficking in Oral Lichen Planus via CXCL9/CXCL10 Upregulations in Oral Keratinocytes.
        J Invest Dermatol. 2017; 137: 2396-2406
        • Takada H.
        • Ibaragi S.
        • Eguchi T.
        • Okui T.
        • Obata K.
        • Masui M.
        • et al.
        Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma.
        Int J Oncol. 2017; 51: 625-632
        • Wu M.
        • Li J.
        • Gao Q.
        • Ye F.
        The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases.
        Expert Opin Ther Targets. 2016; 20: 885-901
        • Ishii T.
        • Ruiz-Torruella M.
        • Yamamoto K.
        • Yamaguchi T.
        • Heidari A.
        • Pierrelus R.
        • et al.
        Locally Secreted Semaphorin 4D Is Engaged in Both Pathogenic Bone Resorption and Retarded Bone Regeneration in a Ligature-Induced Mouse Model of Periodontitis.
        Int J Mol Sci. 2022; 23
        • Song Y.
        • Wang L.
        • Li J.
        • Yang F.
        • Gao Y.
        • Song D.
        • et al.
        The Expression of Semaphorin 7A in Human Periapical Lesions.
        J Endod. 2021; 47: 1631-1639
        • Wang L.
        • Song Y.
        • Yi X.
        • Wu C.
        • Guo Q.
        • Zhou X.
        • et al.
        Semaphorin 7A Accelerates the Inflammatory Osteolysis of Periapical Lesions.
        J Endod. 2022;
        • Lin Y.
        • Xing Q.
        • Qin W.
        • de Melo M.A.S.
        • Zou R.
        • Xu M.
        • et al.
        Decreased Expression of Semaphorin3A/Neuropilin-1 Signaling Axis in Apical Periodontitis.
        Biomed Res Int. 2017; 20178724503
        • Maleki K.T.
        • Cornillet M.
        • Björkström N.K.
        Soluble SEMA4D/CD100: A novel immunoregulator in infectious and inflammatory diseases.
        Clin Immunol. 2016; 163: 52-59
        • Yang S.
        • Wang L.
        • Pan W.
        • Bayer W.
        • Thoens C.
        • Heim K.
        • et al.
        MMP2/MMP9-mediated CD100 shedding is crucial for inducing intrahepatic anti-HBV CD8 T cell responses and HBV clearance.
        J Hepatol. 2019; 71: 685-698
        • Wang H.M.
        • Zhang X.H.
        • Ye L.Q.
        • Zhang K.
        • Yang N.N.
        • Geng S.
        • et al.
        Insufficient CD100 shedding contributes to suppression of CD8(+) T-cell activity in non-small cell lung cancer.
        Immunology. 2020; 160: 209-219
        • Li M.
        • O'Sullivan K.M.
        • Jones L.K.
        • Semple T.
        • Kumanogoh A.
        • Kikutani H.
        • et al.
        CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis.
        J Immunol. 2006; 177: 3406-3412
        • Li Y.
        • Qin L.
        • Bai Q.
        • Zhang J.
        • Chen R.
        • Song K.
        CD100 modulates cytotoxicity of CD8(+) T cells in patients with acute myocardial infarction.
        BMC Immunol. 2021; 22: 13
        • Shi W.
        • Kumanogoh A.
        • Watanabe C.
        • Uchida J.
        • Wang X.
        • Yasui T.
        • et al.
        The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice.
        Immunity. 2000; 13: 633-642
        • Taniuchi I.
        CD4 Helper and CD8 Cytotoxic T Cell Differentiation.
        Annu Rev Immunol. 2018; 36: 579-601
        • Pavlasova G.
        • Mraz M.
        The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy.
        Haematologica. 2020; 105: 1494-1506
        • Bankhead P.
        • Loughrey M.B.
        • Fernández J.A.
        • Dombrowski Y.
        • McArt D.G.
        • Dunne P.D.
        • et al.
        QuPath: Open source software for digital pathology image analysis.
        Sci Rep. 2017; 716878
        • Wang L.
        • Yang F.
        • Qiu Y.
        • Ye L.
        • Song D.
        • Huang D.
        The Potential Roles of T Cells in Periapical Lesions.
        J Endod. 2022; 48: 70-79
        • Cavalla F.
        • Letra A.
        • Silva R.M.
        • Garlet G.P.
        Determinants of Periodontal/Periapical Lesion Stability and Progression.
        J Dent Res. 2021; 100: 29-36
        • Nishide M.
        • Nojima S.
        • Ito D.
        • Takamatsu H.
        • Koyama S.
        • Kang S.
        • et al.
        Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.
        Ann Rheum Dis. 2017; 76: 1440-1448
        • Zhang C.
        • Qiao H.
        • Guo W.
        • Liu Y.
        • Yang L.
        • Liu Y.
        • et al.
        CD100-plexin-B1 induces epithelial-mesenchymal transition of head and neck squamous cell carcinoma and promotes metastasis.
        Cancer Lett. 2019; 455: 1-13
        • Leah E.
        Bone: Finding that osteoclasts repel osteoblast activity through Sema4D reveals novel target for bone-boosting therapies.
        Nat Rev Rheumatol. 2011; 7: 681
        • Ihan Hren N.
        • Ihan A.
        T lymphocyte activation and cytokine expression in periapical granulomas and radicular cysts.
        Arch Oral Biol. 2009; 54: 156-161
        • Fan R.
        • Sun B.
        • Zhang C.F.
        • Lü Y.L.
        • Xuan W.
        • Wang Q.Q.
        • et al.
        Receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression in chronic apical periodontitis: possible association with inflammatory cells.
        Chin Med J (Engl). 2011; 124: 2162-2166
        • Rodini C.O.
        • Lara V.S.
        Study of the expression of CD68+ macrophages and CD8+ T cells in human granulomas and periapical cysts.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001; 92: 221-227
        • Silva T.A.
        • Garlet G.P.
        • Lara V.S.
        • Martins Jr., W.
        • Silva J.S.
        • Cunha F.Q.
        Differential expression of chemokines and chemokine receptors in inflammatory periapical diseases.
        Oral Microbiol Immunol. 2005; 20: 310-316
        • Weber M.
        • Ries J.
        • Büttner-Herold M.
        • Geppert C.I.
        • Kesting M.
        • Wehrhan F.
        Differences in Inflammation and Bone Resorption between Apical Granulomas, Radicular Cysts, and Dentigerous Cysts.
        J Endod. 2019; 45: 1200-1208
        • Takahashi K.
        Microbiological, pathological, inflammatory, immunological and molecular biological aspects of periradicular disease.
        Int Endod J. 1998; 31: 311-325
        • Settem R.P.
        • Honma K.
        • Chinthamani S.
        • Kawai T.
        • Sharma A.
        B-Cell RANKL Contributes to Pathogen-Induced Alveolar Bone Loss in an Experimental Periodontitis Mouse Model.
        Front Physiol. 2021; 12722859
        • Kolomansky A.
        • Kaye I.
        • Ben-Califa N.
        • Gorodov A.
        • Awida Z.
        • Sadovnic O.
        • et al.
        Anti-CD20-Mediated B Cell Depletion Is Associated With Bone Preservation in Lymphoma Patients and Bone Mass Increase in Mice.
        Front Immunol. 2020; 11561294
        • Suzuki K.
        • Kumanogoh A.
        • Kikutani H.
        CD100/Sema4D, a lymphocyte semaphorin involved in the regulation of humoral and cellular immune responses.
        Cytokine Growth Factor Rev. 2003; 14: 17-24