Mechanism of pathogenesis of imiquimod‐induced skin inflammation in the mouse: A role for interferon‐alpha in dendritic cell activation by imiquimod

Abstract

Topical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing cd-T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis-like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ-induced psoriasis-like skin inflammation in mice. We first confirmed that, together with an increase in IL-17 and IL-22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and proinflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7 À/À mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)-a, IL-23, IL-6 and tumor necrosis factor (TNF)-a. Furthermore, when we analyzed in vitro-generated bone marrow-derived DCs with features similar to TNF-a and inducible nitric oxide synthase (iNOS)-producing DCs, IL-23, IL-6, IL-1b, TNF-a and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co-stimulation with IMQ and IFN-a. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN-a was suggested to be caused by upregulation of TLR7 expression by IFN-a. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasislike skin inflammation are induced by IMQ and IFN-a in a mouse model.

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…Our finding that engaging TLR7 on DCs led to DCs with an increased ability to promote Th17 responses is consistent with several previous reports (15,41,42). However, the TLR7 agonist SA-2 is capable of suppressing the IL-17 response by eliciting IL-10 and IL-10-inducing cytokine prodution by DCs (16).…”

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

“…Its medicinal use has been associated with de novo induction or exacerbation of psoriasis (36)(37)(38). This led to the use of a cream containing IMQ on mice to mimic the inflammatory skin disease (7,29,35,39).…”

“…We hypothesize that patients with rheumatoid arthritis or Crohn's disease on anti-TNF drugs are more vulnerable to developing psoriasis upon, for example, TLR7 activation and will produce excessive and sustained amounts of type I IFNs. Moreover, Ueyama et al (39) described how the effects of IMQ are enhanced in the presence of IFN-a, leading to production of IL-1b, IL-6, IL-23, inducible NO synthase/NO, and TNF. Although TNF can be inhibited by anti-TNF treatment, the afore-mentioned cytokines can lead to increased inflammation in these patients, especially when type I IFNs are already increased in these patients.…”

Effects of nanoparticles with hydrotropic nicotinamide on tacrolimus: permeability through psoriatic skin and antipsoriatic and antiproliferative activities

“…5,29,31,32 Three parameters, including erythema, scaling, and thickening, were assigned independently on a scale from 0 to 4 as follows: 0, none; 1, slight; 2, moderate; 3, marked; 4, very marked. A scoring table with red taints was used to score the level of erythema.…”