Mitochondrial transcription factor A serves as a danger signal by augmenting plasmacytoid dendritic cell responses to DNA.
Plasmacytoid dendritic cells (pDC) are potent APCs known to regulate immune responses to self-Ags, particularly DNA. The mitochondrial fraction of necrotic cells was found to most potently promote human pDC activation, as reflected by type I IFN release, which was dependent upon the presence of mitochondrial DNA and involved TLR9 and receptors for advanced glycation end products. Mitochondrial transcription factor A (TFAM), a highly abundant mitochondrial protein that is functionally and structurally homologous to high mobility group box protein 1, was observed to synergize with CpG-containing oligonucleotide, type A, DNA to promote human pDC activation. pDC type I IFN responses to TFAM and CpG-containing oligonucleotide, type A, DNA indicated their engagement with receptors for advanced glycation end products and TLR9, respectively, and were dependent upon endosomal processing and PI3K, ERK, and NF-κB signaling. Taken together, these results indicate that pDC contribute to sterile immune responses by recognizing the mitochondrial component of necrotic cells and further incriminate TFAM and mitochondrial DNA as likely mediators of pDC activation under these circumstances.
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Mark W
MW
Julian
Guohong
G
Shao
Shengying
S
Bao
Daren L
DL
Knoell
Tracey L
TL
Papenfuss
Zachary C
ZC
VanGundy
Elliott D
ED
Crouser
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018899:CpG Islands / Q000235:genetics / Q000276:immunology*; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005784:Gene Amplification / Q000276:immunology; D056945:Hep G2 Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009336:Necrosis; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D000276:Adjuvants, Immunologic; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D024101:Mitochondrial Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D014157:Transcription Factors; C422562:mitochondrial transcription factor A