A Toll-like receptor 7, 8, and 9 antagonist inhibits Th1 and Th17 responses and inflammasome activation in a model of IL-23-induced psoriasis.
Psoriasis is a chronic inflammatory skin disease that involves the induction of T-helper 1 (Th1) and T-helper 17 (Th17) cell responses and the aberrant expression of proinflammatory cytokines, including IL-1β. Copious evidence suggests that abnormal activation of Toll-like receptors (TLRs) contributes to the initiation and maintenance of psoriasis. We have evaluated an antagonist of TLR7, 8, and 9 as a therapeutic agent in an IL-23-induced psoriasis model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the ear or dorsum. IL-23-induced increase in ear thickness was inhibited in a dose-dependent manner by treatment with antagonist. Histological examination of ear and dorsal skin tissues demonstrated a reduction in epidermal hyperplasia in mice treated with the antagonist. Treatment with antagonist also reduced the induction of Th1 and Th17 cytokines in skin and/or serum, as well as dermal expression of inflammasome components, NLRP3 and AIM2, and antimicrobial peptides. These results indicate that targeting TLR7, 8, and 9 may provide a way to neutralize multiple inflammatory pathways that are involved in the development of psoriasis. The antagonist has the potential for the treatment of psoriasis and other autoimmune diseases.
Idera Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
Weiwen
W
Jiang
Fu-Gang
FG
Zhu
Lakshmi
L
Bhagat
Dong
D
Yu
Jimmy X
JX
Tang
Ekambar R
ER
Kandimalla
Nicola
N
La Monica
Sudhir
S
Agrawal
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D007271:Injections, Intradermal; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000008:administration & dosage / Q000009:adverse effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D011565:Psoriasis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000473:pathology*; D058504:Th17 Cells / Q000473:pathology*; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors*; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors*; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors*
C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D053759:Interleukin-23; D008562:Membrane Glycoproteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D009841:Oligonucleotides; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9