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Cited by 85Immune Response and InflammationAdvanced Glycation End Products researchImmunotherapy and Immune Responses

Mitochondrial Transcription Factor A, an Endogenous Danger Signal, Promotes TNFα Release via RAGE- and TLR9-Responsive Plasmacytoid Dendritic Cells

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Julian, Mark W., Shao, Guohong, VanGundy, Zachary C., Papenfuss, Tracey L., Crouser, Elliott D.·2013·PLoS ONE
DOI 10.1371/journal.pone.0072354PMC PMC3741150
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Abstract

OBJECTIVE: Mitochondrial transcription factor A (TFAM) is normally bound to and remains associated with mitochondrial DNA (mtDNA) when released from damaged cells. We hypothesized that TFAM, bound to mtDNA (or equivalent CpG-enriched DNA), amplifies TNFα release from TLR9-expressing plasmacytoid dendritic cells (pDCs) by engaging RAGE. MATERIALS AND METHODS: Murine Flt3 ligand-expanded splenocytes obtained from C57BL/6 mice were treated with recombinant human TFAM, alone or in combination with CpG-enriched DNA with subsequent TNFα release measured by ELISA. The role of RAGE was determined by pre-treatment with soluble RAGE or heparin or by employing matching RAGE (-/-) splenocytes. TLR9 signaling was evaluated using a specific TLR9-blocking oligonucleotide and by inhibiting endosomal processing, PI3K and NF-κB. Additional studies examined whether heparin sulfate moieties or endothelin converting enzyme-1 (ECE-1)-dependent recycling of endosomal receptors were required for TFAM and CpG DNA recognition. MAIN RESULTS: TFAM augmented splenocyte TNFα release in response to CpGA DNA, which was strongly dependent upon pDCs and regulated by RAGE and TLR9 receptors. Putative TLR9 signaling pathways, including endosomal acidification and signaling through PI3K and NF-κB, were essential for splenocyte TNFα release in response to TFAM+CpGA DNA. Interestingly, TNFα release depended upon endothelin converting enzyme (ECE)-1, which cleaves and presumably activates TLR9 within endosomes. Recognition of the TFAM-CpGA DNA complex was dependent upon heparin sulfate moieties, and recombinant TFAM Box 1 and Box 2 proteins were equivalent in terms of augmenting TNFα release. CONCLUSIONS: TFAM promoted TNFα release in a splenocyte culture model representing complex cell-cell interactions in vivo with pDCs playing a critical role. To our knowledge, this study is the first to incriminate ECE-1-dependent endosomal cleavage of TLR9 as a critical step in the signaling pathway leading to TNFα release. These findings, and others reported herein, significantly advance our understanding of sterile immune responses triggered by mitochondrial danger signals.

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  • Extracellular mtDNA can enhance leukocyte migration and degranulation, and promotes secretion of TNF-α by plasmacytoid dendritic cells.

    “Moreover, extracellular mtDNA can enhance leukocyte migration and degranulation (32), and promotes the secretion of the pro-inflammatory cytokine TNF-α by plasmacytoid dendritic cells (33).”

    From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [33]

  • TLR9 interaction with mtDNA activates NF-kB signaling and increases pro-inflammatory cytokine expression.

    “Interaction of TLR9 with mtDNA activates the nuclear factor kappa B (NF-jB) signaling and increases the expression of other pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-6, IL-1b (Julian et al, 2013;Yu & Bennett, 2014;Zhang et al, 2014).”

    From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Julian et al, 2013

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Authors
Julian, M. W., Shao, G., VanGundy, Z. C., Papenfuss, T. L., & Crouser, E. D.
Affiliations
  • The Ohio State University Wexner Medical Center (US)
  • The Ohio State University (US)
Corresponding author
Crouser, Elliott D.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-08-12
Volume
8
Issue
8
Pages
e72354
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0072354
PMC
PMC3741150
OpenAlex
W2055098747
Cited by
85
References
53
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 8 · 2015: 9 · 2014: 5
FWCI
4.05
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R21AI083912, R03 AI62740, R03AI062740)
  • Dorothy M. Davis Heart and Lung Research Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
TFAM, mitochondrial DNA, endogenous danger signals, plasmacytoid dendritic cells, RAGE, TLR9, CpG DNA, endothelin-converting enzyme-1, heparin sulfate, endosomal processing, phosphatidylinositol 3-kinase, NF-κB, sterile inflammation
MeSH terms
Animals, Cell Line, Dendritic Cells, DNA-Binding Proteins, DNA, Mitochondrial, Humans, Male, Models, Biological, Protein Binding, Spleen, Transcription Factors, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, CpG Islands, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Mitochondrial Proteins, HMGB1 Protein, HMGB2 Protein, Toll-Like Receptor 9, Mice

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