TY - JOUR
T1 - Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus
AU - Caielli, Simone
AU - Athale, Shruti
AU - Domic, Bojana
AU - Murat, Elise
AU - Chandra, Manjari
AU - Banchereau, Romain
AU - Baisch, Jeanine
AU - Phelps, Kate
AU - Clayton, Sandra
AU - Gong, Mei
AU - Wright, Tracey
AU - Punaro, Marilynn
AU - Palucka, Karolina
AU - Guiducci, Cristiana
AU - Banchereau, Jacques
AU - Pascual, Virginia
N1 - Publisher Copyright:
© 2016 Caielli et al.
PY - 2016/5/2
Y1 - 2016/5/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84969263240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84969263240&partnerID=8YFLogxK
U2 - 10.1084/jem.20151876
DO - 10.1084/jem.20151876
M3 - Article
C2 - 27091841
AN - SCOPUS:84969263240
SN - 0022-1007
VL - 213
SP - 697
EP - 713
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -