Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear factor κB and its ligand signalling in rheumatoid arthritis.
Rheumatology. 2017-03-13; 56(7): 1200-1205
DOI: 10.1093/rheumatology/kex041
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1. Rheumatology (Oxford). 2017 Jul 1;56(7):1200-1205. doi:
10.1093/rheumatology/kex041.
Neutrophil-derived mitochondrial DNA promotes receptor activator of nuclear
factor κB and its ligand signalling in rheumatoid arthritis.
Contis A(1)(2), Mitrovic S(1)(3), Lavie J(4), Douchet I(1), Lazaro E(1)(5),
Truchetet ME(1), Goizet C(6)(7), Contin-Bordes C(1)(8), Schaeverbeke T(3), Blanco
P(1)(8), Rossignol R(4), Faustin B(1), Richez C(1)(3), Duffau P(1)(2).
Author information:
(1)ImmunoConcept, UMR CNRS 5164, Université de Bordeaux.
(2)Service de médecine interne et immunologie clinique.
(3)Service de rhumatologie, CHU de Bordeaux.
(4)INSERM EA4576, laboratoire MRGM, Université de Bordeaux.
(5)Service de médecine interne, CHU de Bordeaux.
(6)INSERM U1211, laboratoire MRGM, Université de Bordeaux.
(7)Service de génétique médicale.
(8)Laboratoire d’immunologie, CHU de Bordeaux, Bordeaux, France.
Objectives: Mitochondrial DNA (mtDNA) contains sequestered damage-associated
molecular patterns that might be involved in osteoimmunological pathogenesis of
RA. Here, we aimed to investigate the cellular source of mtDNA and its role in
RANK ligand (RANKL) expression by RA SF neutrophils.
Methods: The gene expression signature of SF neutrophils was examined by
proteomic quantitative analysis. Levels of mtDNA in circulating and SF
neutrophils from RA patients and OA control subjects were assessed by real-time
PCR. Purified neutrophils were challenged in vitro with Toll-like receptor
agonists as well as mtDNA. RANKL expression by neutrophils was studied by flow
cytometry.
Results: SF neutrophils from RA patients displayed a gene expression signature of
oxidative stress. This stress signature was associated with the release of mtDNA
in SF as observed by a significant increase of mtDNA in the SF of RA patients
compared with OA patients. mtDNA in RA SF was correlated with systemic
inflammation as assessed by CRP concentrations. We also showed that mtDNA drives
neutrophil RANKL expression to the same extent as Toll-like receptor agonists.
Conclusion: Our data identify SF neutrophils as a cellular source of mtDNA that
leads to a subsequent expression of RANKL. This highlights the important role of
neutrophils in RA osteoimmunology.
© The Author 2017. Published by Oxford University Press on behalf of the British
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DOI: 10.1093/rheumatology/kex041
PMID: 28340056 [Indexed for MEDLINE]