Inhibition of fibulin-3 ameliorates periodontal inflammation through reducing M1 macrophage polarization via EGFR/PI3K/AKT pathway

Hailin Mu; Beining Yang; Yan Wang; Shuo Wang; Wenqian Yu; Meie Jia; Wei Dong; Xinyi Wang; Xiaoxiao Xu; Zhipeng Dong; Baochen Yang; Xuemei Li; Jiawei Wang

doi:10.1002/JPER.24-0405

Inhibition of fibulin-3 ameliorates periodontal inflammation through reducing M1 macrophage polarization via EGFR/PI3K/AKT pathway

J Periodontol. 2024 Dec 18. doi: 10.1002/JPER.24-0405. Online ahead of print.

Authors

Hailin Mu¹, Beining Yang¹, Yan Wang¹, Shuo Wang¹, Wenqian Yu¹, Meie Jia¹, Wei Dong¹, Xinyi Wang¹, Xiaoxiao Xu¹, Zhipeng Dong¹, Baochen Yang¹, Xuemei Li¹, Jiawei Wang¹

Affiliation

¹ State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.

PMID: 39692480
DOI: 10.1002/JPER.24-0405

Abstract

Background: This study aimed to evaluate the role of fibulin-3 (FBLN3) in macrophage polarization, its mechanism, and its effect on periodontitis.

Methods: We conducted studies on periodontitis using both clinical samples and ligature-induced mouse periodontitis model. The inflammatory state was assessed using microcomputed tomography, hematoxylin and eosin staining, immunohistochemical staining, and immunofluorescence staining. In vitro, bone marrow-derived macrophages, and RAW 264.7 macrophages were treated with lipopolysaccharide (LPS) and interleukin (IL)-4 to induce polarization. The role of FBLN3 in macrophage polarization was investigated using overexpression plasmids or siRNAs. Furthermore, local injection of adeno-associated virus was employed to suppress FBLN3 expression in periodontal tissues.

Results: FBLN3 levels were greater in periodontitis tissues. FBLN3 promoted M1 polarization and suppressed M2 polarization in macrophages. The overexpression of FBLN3 promoted M1 polarization via the EGFR/PI3K/AKT signaling pathway, an effect that the epidermal growth factor receptor (EGFR) inhibitor PD153035 reversed. Suppressing FBLN3 expression improved periodontal inflammation and reduced alveolar bone loss in periodontitis.

Conclusions: FBLN3 suppression can mitigate periodontitis by decreasing the M1 macrophage ratio. FBLN3 regulates M1 macrophage polarization through the EGFR/PI3K/AKT signaling pathway.

Plain language summary: Disruption in the collaboration between extracellular matrix (ECM) and immune system is a significant pathology in periodontitis. Macrophages are a crucial part of the immune system and have unique functions, such as polarization. Fibulin-3, an ECM protein, may play a vital role in this dynamic interplay. Fibulin-3 expression is elevated in periodontitis and is closely related to immune cell function. Inhibiting fibulin-3 can alleviate periodontitis by reducing infiltration of immune cells and M1 macrophage ratio. Furthermore, fibulin-3 promoted macrophage M1 polarization by activating the PI3K/AKT signaling pathway through EGFR binding. Our findings offer a clinically relevant rationale for immune response modulation through fibulin-3.

Keywords: EGFR; fibulin‐3 (FBLN3); immune response; macrophage polarization; molecular biology; periodontitis.

Abstract

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