DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis.
Novel therapeutics are required for improving the management of chronic inflammatory diseases. Aptamers are single-stranded RNA or DNA molecules that have recently shown utility in a clinical setting, as they can specifically neutralize biomedically relevant proteins, particularly cell surface and extracellular proteins. The nuclear chromatin protein DEK is a secreted chemoattractant that is abundant in the synovia of patients with juvenile idiopathic arthritis (JIA). Here, we show that DEK is crucial to the development of arthritis in mouse models, thus making it an appropriate target for aptamer-based therapy. Genetic depletion of DEK or treatment with DEK-targeted aptamers significantly reduces joint inflammation in vivo and greatly impairs the ability of neutrophils to form neutrophil extracellular traps (NETs). DEK is detected in spontaneously forming NETs from JIA patient synovial neutrophils, and DEK-targeted aptamers reduce NET formation. DEK is thus key to joint inflammation, and anti-DEK aptamers hold promise for the treatment of JIA and other types of arthritis.
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nirit
N
Mor-Vaknin
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.|Program in Cancer Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Anjan
A
Saha
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Maureen
M
Legendre
Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892, USA.
Carmelo
0000-0002-7706-1464
C
Carmona-Rivera
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
M Asif
MA
Amin
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bradley J
BJ
Rabquer
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Marta J
MJ
Gonzales-Hernandez
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Julie
J
Jorns
Department of Pediatrics and Communicable Diseases, Division of Pediatric Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Smriti
S
Mohan
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Srilakshmi
S
Yalavarthi
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Dave A
DA
Pai
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Kristine
K
Angevine
Microscopy &Image - Analysis Laboratory, University of Michigan, Ann Arbor, Michigan 48109, USA.
Shelley J
SJ
Almburg
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jason S
JS
Knight
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Barbara S
BS
Adams
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.|VA Medical Service, Department of Internal Medicine/Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48105, USA.
Alisa E
AE
Koch
Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan 48109, USA.
David A
DA
Fox
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
David R
DR
Engelke
Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland 20892, USA.
Mariana J
MJ
Kaplan
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.|Programs in Immunology, Cellular &Molecular Biology, and Cancer Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
David M
DM
Markovitz
D000328:Adult; D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D001171:Arthritis, Juvenile / Q000276:immunology / Q000628:therapy*; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D065206:Extracellular Traps / Q000276:immunology* / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D061251:Primary Cell Culture; D013582:Synovial Fluid / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D015054:Zymosan / Q000276:immunology
D052157:Aptamers, Nucleotide; D002630:Chemotactic Factors; D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D015054:Zymosan