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