Psoriasis Triggered by Toll-like Receptor 7 Agonist Imiquimod in the Presence of Dermal Plasmacytoid Dendritic Cell Precursors

Abstract

Background: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. Observations:We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are pres-ent in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. Conclusions:This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.

Aldara activates TLR7-independent immune defence

“…Indeed, topical application of Aldara results in increased infiltration of pDCs, a cell type that expresses high levels of TLR7 and is the main producer of type I interferon (IFN) 6 . Furthermore, Aldara induces local psoriasis-like symptoms in susceptible humans and in mice, such as inflammation, thickening and scaling of the skin [20][21][22] . To determine whether these depend on TLR7 and type I IFN, we topically treated shaved back skin of naive WT129, A129, C57BL/6 and TLR7-knockout (ko) mice with Aldara and analysed epidermal thickness, keratinocyte proliferation and differentiation.…”

“…Psoriasis-like lesions occur in susceptible patients with NMSC as a side effect of Aldara therapy 20,21 . Currently, repeated topical application of Aldara is considered a valuable mouse model for psoriasis 22 , which is an inflammatory and hyperproliferative condition of the skin.…”

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

“…Previous studies reported an essential role for pDCs in the initiation of psoriasis as they transiently infiltrate early lesions and flare-ups of psoriasis upon topical application of Aldara/IMQ (2,8). Established psoriasis lesions however, lack this marked influx of pDCs, suggesting a sequential role for different DC populations during cutaneous disease (22,27,28).…”

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

“…Epidermal deletion of JunB and c-Jun (26), the absence of endogenous MHC class II (27) in inbred mice, or reduced expression of the common chain of β2 integrin in CD18 hypomorphic PL/J mice (28) led to PsA-like disease symptoms. On the other hand, TLR7 ligation in innate immune cells by imiquimod, triggered Ps symptoms (29), while targeting of intracellular adhesion molecule-1 ameliorated the disease (30).…”