Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

Caielli, Simone; Athale, Shruti; Domic, Bojana; Murat, Elise; Chandra, Manjari; Banchereau, Romain; Baisch, Jeanine; Phelps, Kate; Clayton, Sandra; Gong, Mei; Wright, Tracey; Punaro, Marilynn; Palucka, Karolina; Guiducci, Cristiana; Banchereau, Jacques; Pascual, Virginia

doi:10.1084/jem.20151876

Cited by 392 publications

(326 citation statements)

References 52 publications

(67 reference statements)

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“…The possibility that PAD inhibition may act through mechanisms different from NETosis was not considered. In the case of SLE, cumulative evidence now suggests that NETosis is not involved in the disease pathogenesis, as discussed below (19, 99, 100). Thus, the demonstrated benefits of PAD inhibition in experimental models of lupus, attributed to a decreased burden of NETosis (18, 101), may indeed be mediated by alternative mechanisms, such as the transcriptional regulation of anti-inflammatory pathways by these inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it is utilized by some pathogenic bacteria to abrogate neutrophil activity. A third process that can readily be confused with NETosis is the extracellular release of mitochondrial DNA (mtDNA), which results from a constitutive defect in mitophagy in neutrophils (19). This process has not been associated with protein citrullination.…”

Section: Introductionmentioning

confidence: 99%

“…This process has not been associated with protein citrullination. However, it is linked to the production of extracellular oxidized mtDNA (ox-mtDNA), which is highly interferogenic and initially confounded with NETosis in SLE (19). The need for a biochemical definition of NETs and their distinction from other mechanisms of neutrophil damage based on their antimicrobial and pathogenic effects will be discussed.…”

Section: Introductionmentioning

confidence: 99%

“…However, while most cells use an autophagic process called mitophagy to remove damaged mitochondria, recent evidence demonstrated that mitophagy is defective in neutrophils (19). To compensate this problem, neutrophils employ two complementary pathways to achieve mitochondrial clearance.…”

Section: Introductionmentioning

confidence: 99%

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A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination

2016

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NETosis, an antimicrobial form of neutrophil cell death, is considered a primary source of citrullinated autoantigens in rheumatoid arthritis (RA) and immunogenic DNA in systemic lupus erythematosus (SLE). Activation of the citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is believed to be essential for neutrophil extracellular trap (NET) formation and NETosis. PAD4 is therefore viewed as a promising therapeutic target to inhibit the formation of NETs in both diseases. In this review, we examine the evidence for PAD4 activation during NETosis and provide experimental data to suggest that protein citrullination is not a universal feature of NETs. We delineate two distinct biological processes, leukotoxic hypercitrullination (LTH) and defective mitophagy, which have been erroneously classified as “NETosis.” While these NETosis mimics share morphological similarities with NETosis (i.e., extracellular DNA release), they are biologically distinct. As such, these processes can be readily classified by their stimuli, activation of distinct biochemical pathways, the presence of hypercitrullination, and antimicrobial effector function. NETosis is an antimicrobial form of cell death that is NADPH oxidase-dependent and not associated with hypercitrullination. In contrast, LTH is NADPH oxidase-independent and not bactericidal. Rather, LTH represents a bacterial strategy to achieve immune evasion. It is triggered by pore-forming pathways and equivalent signals that cumulate in calcium-dependent hyperactivation of PADs, protein hypercitrullination, and neutrophil death. The generation of citrullinated autoantigens in RA is likely driven by LTH, but not NETosis. Mitochondrial DNA (mtDNA) expulsion, the result of a constitutive defect in mitophagy, represents a second NETosis mimic. In the presence of interferon-α and immune complexes, this process can generate highly interferogenic oxidized mtDNA, which has previously been mistaken for NETosis in SLE. Distinguishing NETosis from LTH and defective mitophagy is paramount to understanding the role of neutrophil damage in immunity and the pathogenesis of human diseases. This provides a framework to design specific inhibitors of these distinct biological processes in human disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination

2016

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“…As a result, the NLRP3 inflammasome can be triggered by mtDNA outside the mitochondria (Lu et al, 2014). In neutrophils, mitochondrial damage may also lead to extrusion of mtDNA nucleiods, which when oxidized, can trigger interferon production and contribute to autoimmune processes in lupus (Caielli et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

The rise of mitochondria in medicine

2016

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Once considered exclusively the cell's powerhouse, mitochondria are now recognized to perform multiple essential cellular functions beyond energy production, impacting most areas of cell biology and medicine. Since the emergence of molecular biology and the discovery of pathogenic mitochondrial DNA defects in the 1980's, research advances have revealed a number of common human diseases which share an underlying pathogenesis involving mitochondrial dysfunction. Mitochondria undergo function-defining dynamic shape changes, communicate with each other, regulate gene expression within the nucleus, modulate synaptic transmission within the brain, release molecules that contribute to oncogenic transformation and trigger inflammatory responses systemically, and influence the regulation of complex physiological systems. Novel “mitopathogenic” mechanisms are thus being uncovered across a number of medical disciplines including genetics, oncology, neurology, immunology, and critical care medicine. Increasing knowledge of the bioenergetic aspects of human disease has provided new opportunities for diagnosis, therapy, prevention, and in connecting various domains of medicine. In this article, we overview specific aspects of mitochondrial biology that have contributed to – and likely will continue to enhance the progress of modern medicine.

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The TFAMoplex—Conversion of the Mitochondrial Transcription Factor A into a DNA Transfection Agent

2022

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Non‐viral gene delivery agents, such as cationic lipids, polymers, and peptides, mainly rely on charge‐based and hydrophobic interactions for the condensation of DNA molecules into nanoparticles. The human protein mitochondrial transcription factor A (TFAM), on the other hand, has evolved to form nanoparticles with DNA through highly specific protein‐protein and protein‐DNA interactions. Here, the properties of TFAM are repurposed to create a DNA transfection agent by means of protein engineering. TFAM is covalently fused to Listeria monocytogenes phospholipase C (PLC), an enzyme that lyses lipid membranes under acidic conditions, to enable endosomal escape and human vaccinia‐related kinase 1 (VRK1), which is intended to protect the DNA from cytoplasmic defense mechanisms. The TFAM/DNA complexes (TFAMoplexes) are stabilized by cysteine point mutations introduced rationally in the TFAM homodimerization site, resulting in particles, which show maximal activity when formed in 80% serum and transfect HeLa cells in vitro after 30 min of incubation under challenging cell culture conditions. The herein developed TFAM‐based DNA scaffolds combine interesting characteristics in an easy‐to‐use system and can be readily expanded with further protein factors. This makes the TFAMoplex a promising tool in protein‐based gene delivery.

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Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

Abstract: As an alternative to mitophagy, neutrophils spontaneously extrude mitochondrial (mt) DNA devoid of oxidized residues (Ox). Activated lupus neutrophils or healthy neutrophils treated with IFN/αRNP release ox-mtDNA bound to TFAM, which induces high levels of IFN-α in pDCs.

Cited by 392 publications

References 52 publications

A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination

A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination

The rise of mitochondria in medicine

The TFAMoplex—Conversion of the Mitochondrial Transcription Factor A into a DNA Transfection Agent

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