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

Abstract

BackgroundThis study aimed to evaluate the role of fibulin‐3 (FBLN3) in macrophage polarization, its mechanism, and its effect on periodontitis.MethodsWe 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.ResultsFBLN3 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.ConclusionsFBLN3 suppression can mitigate periodontitis by decreasing the M1 macrophage ratio. FBLN3 regulates M1 macrophage polarization through the EGFR/PI3K/AKT signaling pathway.Plain language summaryDisruption 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.