Abstract
Loss of periodontal ligament fibroblasts (PDLFs) is one critical issue for regenerating lost periodontal tissues. A wide variety of regulated cell death pathways, such as apoptosis, pyroptosis, and necroptosis have been proposed in the periodontitis development. The aim of the present study was to explore whether long-term periodontitis-level butyrate may trigger ferroptosis, a newly characterized iron-dependent regulated cell death in PDLFs. Here, we showed that long-term treatment of butyrate, an important short-chain fatty acid in the periodontal pocket, induces the cargo receptor nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis in PDLFs. Butyrate-induced iron accumulation, reactive oxygen species (ROS) generation, glutathione depletion and lipid peroxidation in PDLFs, and the butyrate-induced ferroptosis can be blocked by the lipid peroxide scavenger ferrostatin-1. The NCOA4-mediated ferritinophagy is dependent on p38/hypoxia inducible factor-1α (HIF-1α) pathway activation as well as Bromodomain-containing protein (BRD) 4 and cyclin-dependent kinase 9 (CDK9) coordination. These lines of evidence provide a new mechanistic insight into the mechanism of loss of PDLFs during periodontitis development, showing that periodontitis-level butyrate disrupted iron homeostasis by activation of NCOA4-mediated ferritinophagy, leading to ferroptosis in PDLFs.
Highlights
Periodontitis, an inflammatory disease that affects the supporting tissues of the teeth, is initiated by the dysbiosis of dental biofilms in the periodontal milieu[1]
Hereby we discovered that periodontitis-level sodium butyrate treatment-induced ferroptosis in periodontal ligament fibroblasts (PDLFs), and the onset of ferroptosis is closely correlated with activation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy; the p38/hypoxia inducible factor-1α (HIF-1α) pathway activation as well as bromodomain-containing protein (BRD) 4 and cyclin-dependent kinase 9 (CDK9) coordination regulated onset of ferritinophagy and ferroptosis
We previously reported that necroptosis participated in the P. gingivalis-triggered cell death in
Summary
Periodontitis, an inflammatory disease that affects the supporting tissues of the teeth, is initiated by the dysbiosis of dental biofilms in the periodontal milieu[1]. Persistent growth and proliferation of anaerobic periodontal pathogens, such as Porphyromonas gingivalis, Fusobacterium nucleatum, Tannerella forsythia, and Prevotella intermedia, may produce large amounts of shortchain fatty acids (SCFAs), including succinic acid, lactic acid, acetic acid, and butyrate. Periodontitis-level butyrate plays a detrimental role in the periodontal tissues. It may inhibit fibroblast cell growth and proliferation, elicit oxidative stress as well as endoplasmic reticulum stress[8], pyroptosis[9], and apoptosis[10]. The periodontal ligament fibroblasts (PDLFs) can maintain the homeostasis of periodontal ligament through its proliferation and differentiation, persistent detrimental stimuli may lead to irreversible loss of the resident PDLFs
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