Abstract
Necroptosis is a form of cell death that is reportedly involved in the pathogenesis of periodontitis. The role of Mlkl-involved necroptosis remains unclear. Herein, this project aimed to explore the role of MLKL-mediated necroptosis in periodontitis in vitro and in vivo. Expression of RIPK3, MLKL, and phosphorylated MLKL was observed in gingival tissues obtained from healthy subjects or patients with periodontitis. The cell viability of Porphyromonas gingivalis lipopolysaccharide (LPS-Pg)-treated cells was detected. In wild type or Mlkl deficiency mice with ligature-induced periodontitis, alveolar bone loss and osteoclast activation were assessed. mRNA levels of inflammatory cytokines in bone marrow-derived macrophages were tested by qRT-PCR. Increased expression of RIPK3, MLKL, and phosphorylated MLKL was observed in gingival tissues obtained from patients with periodontitis. Porphyromonas gingivalis lipopolysaccharide (LPS-Pg)-treated cells developed necroptosis after caspase inhibition and negatively regulated the NF-κB signaling pathway. In mice with ligature-induced periodontitis, Mlkl deficiency reduced alveolar bone loss and weakened osteoclast activation. Furthermore, genetic ablation of Mlkl in LPS-Pg-treated bone marrow-derived macrophages increased the mRNA levels of tumor necrosis factor-α, interleukin (Il)-1β, Il-6, cyclooxygenase 2, matrix metalloproteinase 9, and receptor activator of nuclear factor kappa-B ligand. Our data indicated that MLKL-mediated necroptosis aggravates the development of periodontitis in a Mlkl-deficient mouse. This will provide a new sight for the understanding of etiology and therapies of periodontitis. KEY MESSAGES: MLKL expression was up-regulated in inflamed human gingival tissue. Mlkl deficiency affected the progression of periodontitis. Necroptosis played a major role in mice periodontitis model. Knockout of Mlkl had a significant effect on inflammatory responses.
Highlights
Periodontitis, a chronic inflammatory disease induced by a pathogenic periodontal microbiome, leads to destruction of the periodontium
The upregulation of proteins belonging to the necroptosis machinery, such as Receptor interacting protein kinase 3 (RIPK3) and, Mixed lineage kinase domain-like pseudokinase (MLKL) and Phosphorylation of MLKL (p-MLKL), is a strong indication of necroptosis [32]
We evaluated protein and transcript levels of RIPK3, MLKL, and p-MLKL in gingival tissues from healthy subjects and patients with periodontitis using western blots and qRT-PCR
Summary
Periodontitis, a chronic inflammatory disease induced by a pathogenic periodontal microbiome, leads to destruction of the periodontium. The prevalence of periodontitis is as high as 45–50%, the severe periodontitis affects 11.2% of the world's population [1]. It is one of the major oral diseases and affects about half of the adult population worldside [2]. Periodontal homeostasis is achieved by intricate regulatory mechanisms functioning in concert [5]. Cell proliferation and cell death are two essential processes in maintaining homeostasis in metazoans, and disturbances in these processes may lead to disease development
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