Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.
Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.
Baylor Institute for Immunology Research, Dallas, TX 75204.
Simone
S
Caielli
Baylor Institute for Immunology Research, Dallas, TX 75204.
Shruti
S
Athale
Baylor Institute for Immunology Research, Dallas, TX 75204.
Bojana
B
Domic
Baylor Institute for Immunology Research, Dallas, TX 75204.
Elise
E
Murat
Baylor Institute for Immunology Research, Dallas, TX 75204.
Manjari
M
Chandra
Baylor Institute for Immunology Research, Dallas, TX 75204.
Romain
R
Banchereau
Baylor Institute for Immunology Research, Dallas, TX 75204.
Jeanine
J
Baisch
Live Cell Imaging Core, University of Texas Southwestern Medical Center, Dallas, TX 75263.
Kate
K
Phelps
Baylor Institute for Immunology Research, Dallas, TX 75204.
Sandra
S
Clayton
Dynavax Technologies Corporation, Berkeley, CA 94710.
Mei
M
Gong
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75263 Texas Scottish Rite Hospital for Children, Dallas, TX 75219.
Tracey
T
Wright
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75263 Texas Scottish Rite Hospital for Children, Dallas, TX 75219.
Marilynn
M
Punaro
Baylor Institute for Immunology Research, Dallas, TX 75204 The Jackson Laboratory Institute for Genomic Medicine, Farmington, CT 06030.
Karolina
K
Palucka
Dynavax Technologies Corporation, Berkeley, CA 94710.
Cristiana
C
Guiducci
The Jackson Laboratory Institute for Genomic Medicine, Farmington, CT 06030.
Jacques
J
Banchereau
Baylor Institute for Immunology Research, Dallas, TX 75204 Texas Scottish Rite Hospital for Children, Dallas, TX 75219 Virginia.Pascual@BSWHealth.org.
Virginia
V
Pascual
D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000276:immunology; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000276:immunology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010084:Oxidation-Reduction; D051199:Toll-Like Receptor 7 / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology
D001323:Autoantibodies; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D024101:Mitochondrial Proteins; C499631:TFAM protein, human; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D014157:Transcription Factors