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Sema3A Drives Alternative Macrophage Activation in the Resolution of Periodontitis via PI3K/AKT/mTOR Signaling

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Abstract

Macrophages actively participate in immunomodulatory processes throughout periodontal inflammation. Regulation of M1/M2 polarization affects macrophage chemokine and cytokine secretion, resulting in a distinct immunological status that influences prognosis. Semaphorin 3A (Sema3A), a neurite growth factor, exerts anti-inflammatory effects. In this study, we investigated the immunomodulation of Sema3A on macrophage-related immune responses in vivo and in vitro. Topical medications of Sema3A in mice with periodontitis alleviated inflammatory cell infiltration into gingival tissue and reduced areas with positive IL-6 and TNFα expression. We observed that the positive area with the M2 macrophage marker CD206 increased and that of the M1 macrophage marker iNOS decreased in Sema3A-treated mice. It has been postulated that Sema3A alleviates periodontitis by regulating alternative macrophage activation. To understand the mechanism underlying Sema3A modulation of macrophage polarization, an in vitro macrophage research model was established with RAW264.7 cells, and we demonstrated that Sema3A promotes LPS/IFNγ-induced M1 macrophages to polarize into M2 macrophages and activates the PI3K/AKT/mTOR signaling pathways. Inhibition of the PI3K signaling pathway activation might reduce anti-inflammatory activity and boost the expression of the inflammatory cytokines, iNOS, IL-12, TNFα, and IL-6. This study indicated that Sema3A might be a feasible drug to regulate alternative macrophage activation in the inflammatory response and thus alleviate periodontitis.

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DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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ACKNOWLEDGEMENTS

Dr. Leyi Chen especially thanks Dr. Jingying Chen (0000-0002-7617-5902) for his help with slide scanning and instructions on immunohistochemistry.

Funding

This study was supported by the Oral Infectious Disease Mechanism Research and Clinical Translation Application Innovation Team of Guangdong Province of China (2021KCXTD033 to Buling Wu) and the President Foundation of Shenzhen Stomatology Hospital (Pingshan), Southern Medical University (2022A001 to Buling Wu).

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Author notes

  1. Tian Tian and Leyi Chen are the co-first authors who contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Endodontics, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, No. 143, Dongzong Road, Pingshan District, Shenzhen, 518118, China

    Tian Tian, Leyi Chen, Mingqi Zhu & Buling Wu

  2. Department of Pediatric Dentistry, Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, No. 143, Dongzong Road, Pingshan District, Shenzhen, 518118, China

    Ziting Wang & Wenan Xu

  3. School of Stomatology, Southern Medical University, Guangzhou, China

    Leyi Chen, Ziting Wang, Mingqi Zhu, Wenan Xu & Buling Wu

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Contributions

TT, WAX, and BLW conceived and designed the experiments. LYC completed most of the animal experiments and wrote the original draft. TT finished the in vitro experiment and drafted the final manuscript and review. ZTW collected and analyzed the data. TT and MQZ helped with some of the immunochemistry staining. All the authors reviewed and approved the final draft of the manuscript.

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Correspondence to Wenan Xu or Buling Wu.

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Animal experiments were approved and conducted in accordance with the guidelines established by Shenzhen TOP Biotechnology Company (TOP-IACUC-2021–0107).

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Summary

Sema3A exerts an ameliorative effect on LPS-induced periodontitis in mice by regulating the alternative polarization of macrophages.

The original online version of this article was revised: The statement "Tian Tian and Leyi Chen are the co-first authors who contributed equally to this work and share first authorship." should be captured as article note.

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Tian, T., Chen, L., Wang, Z. et al. Sema3A Drives Alternative Macrophage Activation in the Resolution of Periodontitis via PI3K/AKT/mTOR Signaling. Inflammation 46, 876–891 (2023). https://doi.org/10.1007/s10753-022-01777-z

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