scholarly journals Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice

2020 ◽  
Vol 7 (1) ◽  
pp. e000387 ◽  
Author(s):  
Karen A Fortner ◽  
Luz P Blanco ◽  
Iwona Buskiewicz ◽  
Nick Huang ◽  
Pamela C Gibson ◽  
...  
Keyword(s):  
T Cells ◽  
Renal Damage ◽  
Immune Therapy ◽  
Type I ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Autoantibody Production ◽  
Mitochondrial Oxidative Stress ◽  
Extracellular Traps ◽  
Immune Complex Formation

ObjectivesRecent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.MethodsLupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.ResultsMitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .ConclusionsThese findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

scholarly journals Protein Kinase D Mediates Mitochondrion-to-Nucleus Signaling and Detoxification from Mitochondrial Reactive Oxygen Species

2005 ◽  
Vol 25 (19) ◽  
pp. 8520-8530 ◽  
Author(s):  
Peter Storz ◽  
Heike Döppler ◽  
Alex Toker
Keyword(s):  
Reactive Oxygen Species ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Reactive Oxygen ◽  
Protein Kinase D ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Oxidative Stress ◽  
Cellular Survival ◽  
Mitochondrial Ros

ABSTRACT Efficient elimination of mitochondrial reactive oxygen species (mROS) correlates with increased cellular survival and organism life span. Detoxification of mitochondrial ROS is regulated by induction of the nuclear SOD2 gene, which encodes the manganese-dependent superoxide dismutase (MnSOD). However, the mechanisms by which mitochondrial oxidative stress activates cellular signaling pathways leading to induction of nuclear genes are not known. Here we demonstrate that release of mROS activates a signal relay pathway in which the serine/threonine protein kinase D (PKD) activates the NF-κB transcription factor, leading to induction of SOD2. Conversely, the FOXO3a transcription factor is dispensable for mROS-induced SOD2 induction. PKD-mediated MnSOD expression promotes increased survival of cells upon release of mROS, suggesting that mitochondrion-to-nucleus signaling is necessary for efficient detoxification mechanisms and cellular viability.

scholarly journals Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Marine Oberkampf ◽  
Camille Guillerey ◽  
Juliette Mouriès ◽  
Pierre Rosenbaum ◽  
Catherine Fayolle ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Reactive Oxygen ◽  
Plasmacytoid Dendritic Cells ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

scholarly journals Spontaneous CD4+ T Cell Activation and Differentiation in Lupus-Prone B6.Nba2 Mice Is IFNAR-Independent

2022 ◽  
Vol 23 (2) ◽  
pp. 874
Author(s):  
Emma J. Keller ◽  
Nina Dvorina ◽  
Trine N. Jørgensen
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Type I ◽  
Autoantibody Production

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated T and B lymphocytes. Type I interferons (IFN-I) have been shown to play important pathogenic roles in both SLE patients and mouse models of lupus. Recent studies have shown that B cell intrinsic responses to IFN-I are enough to drive B cell differentiation into autoantibody-secreting memory B cells and plasma cells, although lower levels of residual auto-reactive cells remain present. We speculated that IFN-I stimulation of T cells would similarly drive specific T-cell associated lupus phenotypes including the upregulation of T follicular helper cells and Th17, thereby affecting autoantibody production and the development of glomerulonephritis. Using the B6.Nba2 mouse model of lupus, we evaluated disease parameters in T cell specific IFN-I receptor (IFNAR)-deficient mice (cKO). Surprisingly, all measured CD4+ T cell abnormalities and associated intra-splenic cytokine levels (IFNγ, IL-6, IL-10, IL-17, IL-21) were unchanged and thus independent of IFN-I. In contrast B6.Nba2 cKO mice displayed reduced levels of effector CD8+ T cells and increased levels of Foxp3+ CD8+ regulatory T cells, suggesting that IFN-I induced signaling specifically affecting CD8+ T cells. These data suggest a role for both pathogenic and immunosuppressive CD8+ T cells in Nba2-driven autoimmunity, providing a model to further evaluate the role of these cell subsets during lupus-like disease development in vivo.

scholarly journals Nucleated Fish Erythrocyte Extracellular Traps (FEETs) release is an evolutionary conserved immune defence process

2021 ◽  
Author(s):  
Giulia Rinaldi ◽  
Neila Alvarez de Haro ◽  
Andrew Paul Desbois ◽  
Calum T. Robb ◽  
Adriano G. Rossi
Keyword(s):  
Calcium Ionophore ◽  
Innate Immune ◽  
Oxygen Species ◽  
Immune Defence ◽  
Mitochondrial Reactive Oxygen Species ◽  
Antimicrobial Proteins ◽  
Extracellular Traps ◽  
Kinase C ◽  
Innate Immune Defence ◽  
Fish Erythrocyte

Fish erythrocytes remain nucleated for their life-span, unlike mammalian erythrocytes which undergo enucleation. Asides transportation of oxygen, fish erythrocytes are capable of several immune defence processes. Nucleated fish erythrocytes represent prime candidates for carrying out ETotic responses. ETosis is an evolutionary conserved innate immune defence process found in both vertebrates and invertebrates, which involves the extrusion of DNA studded with antimicrobial proteins into the extracellular space serving to trap and kill microorganisms. In this report, we demonstrate that fish erythrocytes isolated from Danio rerio (zebrafish) produce ETotic-like responses when exposed to chemical and physiological stimuli. Salmo salar (Atlantic salmon) erythrocytes produce similar ETotic responses. We have termed these ET-like formations Fish Erythrocyte Extracellular Traps (FEETs). Interestingly, we discovered that mammalian inducers of NETosis, such as the protein kinase C (PKC) activator phorbol 12‐myristate 13‐acetate and the calcium ionophore ionomycin induced FEETs. Moreover, we found that FEETs are dependent upon activation of PKC and generation of mitochondrial reactive oxygen species. Thus, this brief report represents the first demonstration that fish erythrocytes can exhibit ETotic-like responses, unveiling a previously unknown function of nucleated erythrocytes, and sheds new light on the innate immune arsenal of erythrocytes.

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