LiCl‐induced immunomodulatory periodontal regeneration via the activation of the Wnt/β‐catenin signaling pathway

Abstract

BackgroundGrowing evidence suggests that excessive inflammation hampers the regenerative capacity of periodontal ligament cells (PDLCs) and that activation of the Wnt/β‐catenin pathway is crucial in suppressing immune dysregulation.ObjectiveThis study aimed to establish the role of the Wnt/β‐catenin in regulating the immune microenvironment and its subsequent impact on periodontal regeneration.MethodsLithium chloride (LiCl, Wnt activator) was administered daily into the standard periodontal defects created in 12‐week‐old Lewis rats. Harvested at 1‐week and 2‐week post‐surgery, samples were then subjected to histological and immunohistochemical evaluation of macrophage distribution and phenotype (pro‐inflammatory M1 and anti‐inflammatory M2). A murine macrophage cell line, RAW 264.7, was stimulated with LiCl to activate Wnt/β‐catenin. Following treatment with the conditioned medium derived from the LiCl‐activated macrophages, the expression of bone‐ and cementum‐related markers of the PDLCs was determined. The involvement of Wnt/β‐catenin in the immunoregulation and autophagic activity was further investigated with the addition of cardamonin, a commercially available Wnt inhibitor.ResultsA significantly increased number of macrophages were detected around the defects during early healing upon receiving the Wnt/β‐catenin signaling cue. The defect sites in week 2 exhibited fewer M1 and more M2 macrophages along with an enhanced regeneration of alveolar bone and cementum in the Wnt/β‐catenin activation group. LiCl‐induced immunomodulatory effect was accompanied with the activation Wnt/β‐catenin signaling, which was suppressed in the presence of Wnt inhibitor. Exposure to LiCl could induce autophagy in a dose‐dependent manner, thus maintaining macrophages in a regulatory state. The expression level of bone‐ and cementum‐related markers was significantly elevated in PDLCs stimulated with LiCl‐activated macrophages.ConclusionThe application of Wnt activator LiCl facilitates the recruitment of macrophages to defect sites and regulates their phenotypic switching in favor of periodontal regeneration. Suppression of Wnt/β‐catenin pathway could attenuate the LiCl‐induced immunomodulatory effect. Taken together, the Wnt/β‐catenin pathway may be targeted for therapeutic interventions in periodontal diseases.

Plasma‐activated medium triggers immunomodulation and autophagic activity for periodontal regeneration

“…While M2 macrophages produce a proregenerative milieu ideal for periodontal tissue repair and regeneration, inflammatory M1 macrophages inhibit PDLC differentiation and mineralization by secreting a range of proinflammatory cytokines 46,47 . BMP‐2, a member of the transforming growth factor‐β (TGF‐β) super family, is required in initiating the activation of Wnt signaling pathway that promotes the differentiation of PDLCs 4,48–50 . PAM treatment increased BMP‐2 production in M1 macrophage‐derived conditioned medium (Figure 5C,D), suggesting that PAM has the potential to be used in periodontal therapy as an enhancer for osteogenesis and cementogenesis.…”

“…The PDLCs used in this study were harvested from caries‐free and periodontally healthy premolars extracted for orthodontic treatment purposes ( n = 6). The periodontal ligament tissues were isolated from the mid‐third of the tooth root surfaces, trimmed to fine pieces, and rinsed with PBS 4 . The tissue explants were transferred to a T75 flask with DMEM containing 10% FBS and 1% P/S.…”

“…The proinflammatory functions of M1 macrophages include phagocytosing pathogens or foreign particles, presenting antigens to other immune cells, and secreting inflammatory cytokines to trigger the inflammation 3 . However, M1 macrophages would cause chronic inflammation and damage the tissues if they continuously released cytotoxic substances into the microenvironment 4 . Anti‐inflammatory cytokines produced by M2 macrophages, on the other hand, would encourage tissue regeneration 1 .…”

“…Periodontitis, a common bacterial infection‐induced chronic inflammation, often results in tooth loss leading to major aesthetic and functional issues if left untreated 5 . Excessive M1 macrophages and uncontrolled M1 macrophage‐mediated cytokine secretion are the significant factors that cause the destruction of periodontium, including periodontal ligament (PDL), cementum and alveolar bone 4 . Therefore, restoring the balance between M1 and M2 macrophages is essential for periodontitis patients to reduce chronic inflammation and enhance tissue regeneration.…”

Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease

“…However, we can see some possible common mechanisms in other examples of inflammatory diseases. Through the study of periodontal regeneration, it has been shown that Wnt/β-catenin signaling activation can activate macrophage autophagy to promote the transformation to M2 type macrophages and achieve tissue repair [ 120 ]. Negative regulation of Wnt signaling by autophagy promotes the differentiation of Bone-marrow-derived macrophage (BMDM) into osteoclasts, thereby affecting tissue regeneration [ 121 ].…”