Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE

Caielli, Simone; Cardenas, Jacob; Jesús, Adriana Almeida de; Baisch, Jeanine; Walters, Lynnette; Blanck, Jean Philippe; Balasubramanian, Preetha; Stagnar, Cristy; Ohouo, Marina; Hong, Seunghee; Nassi, Lorien; Stewart, Katie; Fuller, Julie; Gu, Junjie; Banchereau, Jacques; Wright, Tracey; Goldbach‐Mansky, Raphaela; Pascual, Virginia

doi:10.1016/j.cell.2021.07.021

Cited by 134 publications

(107 citation statements)

References 85 publications

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“…Supporting these reports, we observed here an increase in autophagosome abundance and size in OrthoE (Figure 5) that might reflect an increase in autophagic activity within the cell. Defect in proper mitochondria degradation leads to the maintenance of mitochondria in mature circulating red blood cells, as recently described for SCD or for SLE (Jagadeeswaran et al, 2017;Caielli et al, 2021;Martino et al, 2021). While not completely elucidated, this defective mitochondrial clearance might participate in the pathophysiology of the diseases.…”

Section: Discussionmentioning

confidence: 79%

“…Mitochondrial retention was previously associated with deficient mitophagy following mitophagy receptors knockdown in mice ( Sandoval et al, 2008 ) and humans ( Moras et al, 2022 ). During the last 5 years, growing evidences were reported correlating autophagy deficiencies and particularly mitophagy defaults with different pathologies as sickle cell disease (SCD) or systemic lupus erythematosus (SLE; Jagadeeswaran et al, 2017 ; Caielli et al, 2021 ; Martino et al, 2021 ). Moreover, a novel atypical anemia was associated with the presence of miscellaneous membranous structure on patients’ reticulocytes and mature red blood ( Ru et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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Throughout mammal erythroid differentiation, erythroblasts undergo enucleation and organelle clearance becoming mature red blood cell. Organelles are cleared by autophagic pathways non-specifically targeting organelles and cytosolic content or by specific mitophagy targeting mitochondria. Mitochondrial functions are essential to coordinate metabolism reprogramming, cell death, and differentiation balance, and also synthesis of heme, the prosthetic group needed in hemoglobin assembly. In mammals, mitochondria subcellular localization and mitochondria interaction with other structures as endoplasmic reticulum and nucleus might be of importance for the removal of the nucleus, that is, the enucleation. Here, we aim to characterize by electron microscopy the changes in ultrastructure of cells over successive stages of human erythroblast differentiation. We focus on mitochondria to gain insights into intracellular localization, ultrastructure, and contact with other organelles. We found that mitochondria are progressively cleared with a significant switch between PolyE and OrthoE stages, acquiring a rounded shape and losing contact sites with both ER (MAM) and nucleus (NAM). We studied intracellular vesicle trafficking and found that endosomes and MVBs, known to be involved in iron traffic and heme synthesis, are increased during BasoE to PolyE transition; autophagic structures such as autophagosomes increase from ProE to OrthoE stages. Finally, consistent with metabolic switch, glycogen accumulation was observed in OrthoE stage.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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“…Moreover, the increasing armamentarium of medications available for the treatment of SLE poses a dilemma as to which to use and the treatment paradigms (e.g., induction, followed by sequential additive or simultaneous additive therapies). For example, a whole blood RT-PCR classifier to classify SLE patients with predominant IFN, plasmablast, neutrophil or erythropoiesis signatures may be warranted before embarking on targeted therapy against certain cytokines or immune cells [ 16 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

“…Advancement in technology has allowed more in-depth gene expression studies to shed light on the molecular pathogenesis of SLE, starting from microarray platforms to RNA sequencing and, more recently, single-cell RNA sequencing [ 16 , 33 , 34 , 35 , 36 , 46 ]. As the technology platforms grew in sophistication, it became important to develop novel strategies to analyze such large scale data [ 47 ].…”

Section: Interferon Pathways Leading To Slementioning

confidence: 99%

“…Anifrolumab is a fully human, IgG1κ monoclonal antibody that binds to type I interferon (IFN) receptor subunit 1 (IFNAR1) to suppress signaling by all type I IFNs [ 14 , 15 ]. This is particularly befitting with the understanding of SLE being a prototype “type I interferonopathy” [ 16 ]. However, the type I IFN landscape has also been littered with a number of negative clinical trials targeting type I IFNs with various agents, including that of anifrolumab itself [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

Sim

Ong

Mak

et al. 2022

IJMS

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Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.

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Combining Cooling Enhancement and Trehalose Dehydration to Enable Scalable Volume Cryopreservation of Red Blood Cells with Low Concentration of Glycerol

et al. 2022

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Enhancing the cooling rate is often an alternative to increasing concentrations of cryoprotectants to inhibit harmful ice growth during freezing. Processing cell suspensions as dispersed droplets can improve the cooling rate but carries the risk of difficult collection and contamination. As the most readily available cells, human red blood cells (RBCs) are used to test the feasibility of advanced cryopreservation techniques. Herein, a feasible and straightforward method for scalable cryopreservation of RBCs is presented. This method can be easily realized by selecting 5 × 6 mm polytetrafluoroethylene (PTFE) tubes with better cooling capacity and applying the trehalose dehydration technique. Finally, the highest freeze‐thaw recovery rate in the available literature with trehalose alone (93.87% with 0.4 m Tre) and freezing the volume of RBCs from 2 to 20 mL with a higher freeze‐thaw recovery of 95–96% after adding 5% glycerol (0.4 m Tre + 5% Gly) are achieved. A two‐step washing method is also evaluated to remove the cryoprotectants, allowing the process could be completed within 20 min after thawing. Furthermore, the functional expression of postwash RBCs after cryopreservation is examined and all results show that this scalable volume cryopreservation method can be extended to current clinical RBC cryopreservation.

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Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE

Cited by 134 publications

References 85 publications

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

Combining Cooling Enhancement and Trehalose Dehydration to Enable Scalable Volume Cryopreservation of Red Blood Cells with Low Concentration of Glycerol

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