Ferroptosis: A New Development Trend in Periodontitis

Abstract

Periodontitis is a chronic inflammatory disease associated with bacterial biofilm. It is characterized by loss of periodontal support tissue and has long been considered as a "silent disease". Because it is difficult to prevent and has a health impact that can not be ignored, researchers have been focusing on a mechanism-based treatment model. Ferroptosis is an iron-dependent regulatory form of cell death, that directly or indirectly affects glutathione peroxidase through different signaling pathways, resulting in a decrease in cell antioxidant capacity, accumulation of reactive oxygen species and lipid peroxidation, which cause oxidative cell death and tissue damage. Recently, some studies have proven that iron overload, oxidative stress, and lipid peroxidation exist in the process of periodontitis. Based on this, this article reviews the relationship between periodontitis and ferroptosis, in order to provide a theoretical reference for future research on the prevention and treatment of periodontal disease.

Keywords: ferroptosis; iron overload; lipid peroxidation; oxidative stress; periodontal pathogen; periodontitis.

Figure 1

The related mechanism of ferroptosis and periodontitis. Glutamate acid and cystine are exchanged in a ratio of 1:1 inside and outside cells, and cystine is reduced to participate in GSH synthesis, activate GPX4, and inhibit ROS production. When VDAC was opened, NADPH production increased, which provided reduced hydrogen for GSH formation but increased ROS production. Tf combines with Tfr and merges into cells, and is introduced into the cytoplasm by DMT1, and exists in two forms of ferritin and free iron. Ferritin autophagy occurs through NCOA4, which increases the content of free iron, causes Fenton reaction and increases ROS. Under oxidative stress, NRF2 initiates the expression of GPX4, HO-1 and ferritin heavy chain, but at the same time, HO-1 can decompose heme to produce ferrous iron. P53 not only inhibits the expression of SLC7A11 but can also target PTGS2, promote prostaglandin synthesis, and damage periodontium. Glutamate was prepared by hydrolysis of glutamine catalyzed by GLS2. LOX promotes the formation of lipid peroxidation in cells. MAPK pathway and hippo pathway promote each other, NF2 activates hippo, activates LATS1/2, phosphorylates YAP and inhibits the expression of downstream ACSL4. In periodontitis, inflammatory factors IL-6, IL-8 and TNF-α can promote the deposition of unsaturated fatty acids, which are acylated by AcSL4, integrated to cell membrane by LPCAT3, and become an important substance of iron death after being oxidized by LOX. TGF-β1 during periodontal bone formation can inhibit the expression of SLC7A11 through Smad3. Abbreviations—Tf, transferrin; TFR, transferrin receptor; DMT1, divalent metal ion transporter 1; NCOA4, nuclear receptor coactivator 4; OH-1, heme oxygenase-1; NRF2, nuclear factor erythroid 2-related factor 2; GSH, glutathione; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; VDAC, voltage-dependent anion channel; TGF-β1, transforming growth factor-β 1; PG, prostaglandin; PTGS2, prostaglandin-endoperoxide synthase 2; LOX, lipoxygenase; LPCAT3, phospholipid choline acyltransferase 3; AA(PUFAs), arachidonic acid (Polyunsaturated fatty acids); AA-CoA, arachidonic acid-coenzyme A; ACSL4, acyl-Coa synthase long-chain family member 4; NF2, neurofibromatosis 2; YAP, Yes-associated protein; MAPK, mitogen-activated protein kinase; TNF-α, tumor Necrosis Factor-α; IL, interleukin; Smad3, Small mothers against decapentaplegic.

Figure 2

Ferroptosis programs in the periodontal microenvironment. In the periodontitis environment, inflammation, HIF, and iron concentration influence intracellular iron homeostasis. Intracellular iron homeostasis is responsible for immune homeostasis. In an inflammatory state, periodontal pathogenic micro-organisms up-regulate iron ion concentration through metabolism. At the same time, inflammation and HIF promote the deposition of PUFA in cells. When intracellular iron homeostasis is unbalanced, the Fenton reaction will occur and reactive oxygen species will be generated to peroxidation of intracellular PUFA and generate lipid peroxides to accelerate the process of cell ferroptosis. Abbreviations—ROS, reactive oxygen species; PUFA, polyunsaturated fatty acids; HIF, hypoxia-inducible factor.