Imiquimod-Induced Psoriasis-Like Skin Inflammation is Suppressed by BET Bromodomain Inhibitor in Mice through RORC/IL-17A Pathway Modulation

Journal Article
Nadeem, Ahmed . 2015
Publication Work Type: 
Journal Article
Tags: 
Imiquimod, psoriasis, BET
Magazine \ Newspaper: 
Pharmacological Research
Issue Number: 
Sep.
Volume Number: 
99
Pages: 
248–257
Publication Abstract: 

Psoriasis is one of the most common skin disorders characterized by  erythematous plaques that 
result
from hyperproliferative keratinocytes and infiltration of inflammatory leukocytes into dermis and 
epi- dermis. Recent studies suggest that IL-23/IL-17A/IL-22 cytokine axis plays an important  role 
in  the pathogenesis of psoriasis. The small molecule bromodomain and extraterminal domain (BET) 
inhibitors, that disrupt interaction of BET proteins with acetylated histones have recently 
demonstrated efficacy in various models of inflammation through suppression of several pathways, one 
of them being synthesis of IL-17A/IL-22 which primarily depends on  transcription factor, retinoic 
acid receptor-related orphan receptor C (RORC). However, the efficacy and mechanistic aspect of a 
BET inhibitor in  mouse model of skin inflammation has not been explored previously. Therefore, this 
study investigated the role of BET inhibitor, JQ-1  in  mouse model of psoriasis-like inflammation. 
Mice were topically applied imiquimod (IMQ)  to develop psoriasis-like inflammation on  the shaved 
back and ear followed by  assessment  of skin inflammation (myeloperoxidase activity, ear thickness, 
and histopathology), RORC and its signature cytokines (IL-17A/IL-22). JQ-1 suppressed IMQ-induced 
skin inflammation as reflected by a decrease in ear thickness/myeloperoxidase activity, and 
RORC/IL-17A/IL-22 expression. Additionally, a RORex/')' ago- nist SR1078 was utilized to 
investigate the role of  RORC in  BET-mediated skin inflammation.  SR1078 reversed the protective 
effect of JQ-1  on  skin inflammation at both histological and molecular levels in the IMQ model. 
The current study suggests that BET bromodomains are involved in psoriasis-like inflam- mation 
through induction of  RORC/IL-17A  pathway. Therefore, inhibition of  BET bromodomains may
provide a new therapy against skin inflammation.