Force-Induced Autophagy in Periodontal Ligament Stem Cells Modulates M1 Macrophage Polarization via AKT Signaling

Nan Jiang; Danqing He; Yushi Ma; Junxiang Su; Xiaowen Wu; Shengjie Cui; Zixin Li; Yanheng Zhou; Huajie Yu; Yan Liu

doi:10.3389/fcell.2021.666631

Force-Induced Autophagy in Periodontal Ligament Stem Cells Modulates M1 Macrophage Polarization via AKT Signaling

Front Cell Dev Biol. 2021 May 26:9:666631. doi: 10.3389/fcell.2021.666631. eCollection 2021.

Authors

Nan Jiang¹, Danqing He², Yushi Ma², Junxiang Su³, Xiaowen Wu³, Shengjie Cui², Zixin Li², Yanheng Zhou², Huajie Yu⁴, Yan Liu²

Affiliations

¹ Central Laboratory, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China.
² Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, China.
³ Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Shanxi, China.
⁴ The Fourth Division, Peking University School and Hospital of Stomatology, Beijing, China.

Abstract

Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.

Keywords: AKT signaling; autophagy; bone remodeling; inflammation; macrophage polarization; mechanical force; periodontal ligament stem cells; tooth movement.