Inhibition of P2X4 suppresses joint inflammation and damage in collagen-induced arthritis.
Recent data have shown that the purinergic receptor P2X4 plays key roles in inflammatory responses. We evaluated whether P2X4 inhibition could affect the development of arthritis and autoimmunity in collagen-induced arthritis (CIA) model. P2X4 antisense oligonucleotide (asODN) was injected intravenously via tail vein into the CIA mice to selectively inhibit P2X4 expression daily for 14 days. P2X4 asODN treatment reduced the clinical score of CIA in mice. P2X4 asODN also decreased the levels of serum IL-1β, TNF-α, IL-6, and IL-17. P2X4 asODN treatment significantly inhibited synovial inflammation and joint destruction. P2X4 asODN treatment also suppressed the NLR family, pyrin domain containing 1 (NLRP1) inflammasome activation in CIA mice and synovial cells of human rheumatoid arthritis. These data show that P2X4 asODN confers a therapeutic benefit on CIA. Inhibition of the NLRP1 inflammasome signaling pathway is the underlying mechanism of action.
Department of Rheumatology, Jinan Central Hospital Affiliated to Shandong University, Jinan, 250013, Shandong, China.
Faxin
F
Li
Nongjian
N
Guo
Yuxia
Y
Ma
Bin
B
Ning
Yan
Y
Wang
Liqing
L
Kou
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D015551:Autoimmunity / Q000187:drug effects; D003094:Collagen; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007249:Inflammation / Q000188:drug therapy*; D019410:Interleukin-16 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D007596:Joints / Q000276:immunology / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D058848:Receptors, Purinergic P2X4 / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D058847:Inflammasomes; D019410:Interleukin-16; D020381:Interleukin-17; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; D020319:Oligodeoxyribonucleotides, Antisense; D058848:Receptors, Purinergic P2X4; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen