Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice.
The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the l-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL(lpr/lpr) mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36-based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.
Kulkarni
Onkar
O
Nephrological Center, Ludwig-Maximilians-University, 80336 Munich, Germany.
Pawar
Rahul D
RD
Purschke
Werner
W
Eulberg
Dirk
D
Selve
Norma
N
Buchner
Klaus
K
Ninichuk
Volha
V
Segerer
Stephan
S
Vielhauer
Volker
V
Klussmann
Sven
S
Anders
Hans-Joachim
HJ
D000818:Animals; D015551:Autoimmunity; D001853:Bone Marrow / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004247:DNA / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D008181:Lupus Nephritis / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000401:mortality / Q000628:therapy; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009000:Monocytes / Q000276:immunology; D009843:Oligoribonucleotides / Q000097:blood / Q000493:pharmacokinetics*; D015996:Survival Rate
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D009843:Oligoribonucleotides; D004247:DNA