Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury

Liu, Jiaye; Gong, Wei

doi:10.3389/fimmu.2021.680648

Cited by 25 publications

(18 citation statements)

References 107 publications

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“…In response to kidney injury, however, they are also able to promote progression of CKD via the synthesis of various bioactive molecules (e.g., cytokines/chemokines, RNAs, DNAs, or proteins) that drive interstitial inflammation and fibrosis. 55,[71][72][73] The transfer of these bioactive molecules into the extracellular milieu can be facilitated via exosomes. For example, Figure 7.…”

Section: Discussionmentioning

confidence: 99%

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

Ranches¹,

Zeidler²,

Kessler³

et al. 2022

Molecular Therapy - Nucleic Acids

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Section: Discussionmentioning

confidence: 99%

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

Ranches¹,

Zeidler²,

Kessler³

et al. 2022

Molecular Therapy - Nucleic Acids

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“…During mitochondrial stress, there is the leakage of mitochondrial (mt) DNA into the cytoplasm [ 53 ]. The mtDNA has been shown to trigger the cGAS-STING signalling and IFN-1 production [ 54 , 55 ]. Hence, the activation of IFN-1 response by cryptolepine independent of STING implies that cryptolepine is not causing substantial cellular and mitochondrial stress.…”

Section: Discussionmentioning

confidence: 99%

The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways

Domfeh

Narkwa

Quaye

et al. 2022

Journal of Immunology Research

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Type 1 interferons (IFN-1) are pleiotropic cytokines with well-established anticancer and antiviral properties, particularly in mucosal tissues. Hence, natural IFN-1-inducing treatments are highly sought after in the clinic. Here, we report for the first time that cryptolepine, a pharmacoactive alkaloid in the medicinal plant Cryptolepis sanguinolenta, is a potent IFN-1 pathway inducer. Cryptolepine increased the transcript levels of JAK1, TYK2, STAT1, STAT2, IRF9, and OAS3, as well as increased the accumulation of STAT1 and OAS3 proteins, similar to recombinant human IFN-α. Cryptolepine effects were observed in multiple cell types including a model of human macrophages. This response was maintained in MAVS and STING-deficient cell lines, suggesting that cryptolepine effects are not mediated by nucleic acids released upon nuclear or organelle damage. In agreement, cryptolepine did not affect cell viability in concentrations that triggered potent IFN-1 activation. In addition, we observed no differences in the presence of a pharmacological inhibitor of TBK1, a pleiotropic kinase that is a converging point for Toll-like receptors (TLRs) and nucleic acid sensors. Together, our results demonstrate that cryptolepine is a strong inducer of IFN-1 response and suggest that cryptolepine-based medications such as C. sanguinolenta extract could be potentially tested in resource-limited regions of the world for the management of chronic viral infections as well as cancers.

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“…Inflammasome allows the activation of caspase-1, and triggers the maturation and secretion of pro-inflammatory cytokines IL-1β/IL-18 [ 42 , 43 ]. NLRP3 inflammasomes are generally located in neutrophils, monocytes, dendritic cells, macrophages, and many non-hematopoietic cells [ 44 , 45 , 46 ].…”

Section: Mtdna As a Danger Signalmentioning

confidence: 99%

Molecular Mechanisms of mtDNA-Mediated Inflammation

Gaetano

Solodka

Zanini

et al. 2021

Cells

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Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.

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Circulating Mitochondrial DNA Stimulates Innate Immune Signaling Pathways to Mediate Acute Kidney Injury

Cited by 25 publications

References 107 publications

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways

Molecular Mechanisms of mtDNA-Mediated Inflammation

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