ABSTRACT
T regulatory (Treg) cells are crucial to maintain immune tolerance and repress antitumor immunity, but the mechanisms governing their cellular redox homeostasis remain elusive. We report that glutathione peroxidase 4 (Gpx4) prevents Treg cells from lipid peroxidation and ferroptosis in regulating immune homeostasis and antitumor immunity. Treg-specific deletion of Gpx4 impairs immune homeostasis without substantially affecting survival of Treg cells at steady state. Loss of Gpx4 results in excessive accumulation of lipid peroxides and ferroptosis of Treg cells upon T cell receptor (TCR)/CD28 co-stimulation. Neutralization of lipid peroxides and blockade of iron availability rescue ferroptosis of Gpx4-deficient Treg cells. Moreover, Gpx4-deficient Treg cells elevate generation of mitochondrial superoxide and production of interleukin-1ß (IL-1ß) that facilitates T helper 17 (TH17) responses. Furthermore, Treg-specific ablation of Gpx4 represses tumor growth and concomitantly potentiates antitumor immunity. Our studies establish a crucial role for Gpx4 in protecting activated Treg cells from lipid peroxidation and ferroptosis and offer a potential therapeutic strategy to improve cancer treatment.
Subject(s)
Ferroptosis , Immunity , Lipid Peroxidation , Lymphocyte Activation/immunology , Neoplasms/immunology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , Cell Line, Tumor , Forkhead Transcription Factors/metabolism , Gene Deletion , Homeostasis , Interleukin-1beta/metabolism , Iron/metabolism , Lipid Peroxides/metabolism , Lymphoid Tissue/immunology , Mice, Inbred C57BL , Mitochondria/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/deficiency , Superoxides/metabolism , Th17 Cells/immunologyABSTRACT
Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer's, Parkinson's, and Huntington's diseases, has also been addressed.
Subject(s)
Alzheimer Disease/metabolism , Ferroptosis , Huntington Disease/metabolism , Iron/metabolism , Neurons/metabolism , Parkinson Disease/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Arachidonate 15-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/metabolism , Arachidonic Acid/metabolism , Brain/metabolism , Brain/pathology , Cell Membrane/metabolism , Cell Membrane/pathology , Fatty Acids, Unsaturated/metabolism , Glutathione/metabolism , Humans , Huntington Disease/genetics , Huntington Disease/pathology , Lipid Peroxidation , Neurons/pathology , Oxidative Stress , Parkinson Disease/genetics , Parkinson Disease/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase/deficiencyABSTRACT
The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-ß-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-ß-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-ß signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.
Subject(s)
Idiopathic Pulmonary Fibrosis/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Animals , Bleomycin , Cell Differentiation , Cells, Cultured , Disease Models, Animal , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/pathology , Lipid Peroxidation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myofibroblasts/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/deficiency , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Transforming Growth Factor beta/metabolismABSTRACT
Huntington's disease (HD) is an autosomal dominant and fatal neurodegenerative disorder, which is caused by an abnormal CAG repeat in the huntingtin gene. Despite its well-defined genetic origin, the molecular mechanisms of neuronal death are unclear yet, thus there are no effective strategies to block or postpone the process of HD. Ferroptosis, a recently identified iron-dependent cell death, attracts considerable attention due to its putative involvement in neurodegenerative diseases. Accumulative data suggest that ferroptosis is very likely to participate in HD, and inhibition of the molecules and signaling pathways involved in ferroptosis can significantly eliminate the symptoms and pathology of HD. This review first describes evidence for the close relevance of ferroptosis and HD in patients and mouse models, then summarizes advances for the mechanisms of ferroptosis involved in HD, finally outlines some therapeutic strategies targeted ferroptosis. Comprehensive understanding of the emerging roles of ferroptosis in the occurrence of HD will help us to explore effective therapies for slowing the progression of this disease.
