4and Fig. the development of skin lesions, whereas treatment with a bifunctional TLR7/9 inhibitor before tape stripping or after the initial lesion was established led to a significant reduction of the disease. These data suggest that inhibitors of TLR7 and TLR9 signaling have potential therapeutic application for the treatment of interface dermatitis. The triggering of TLR7 and TLR9 in plasmacytoid DC (PDC) precursors and B cells by selfnucleic acids is key in the pathogenesis of systemic lupus erythematosus (SLE). This leads to the production of type I IFNs from PDCs that can be detected by the up-regulation of IFN-regulated genes in the blood of patients (IFN signature) and anti-DNA and anti-RNP antibodies from B cells that form immunocomplexes (ICs) with DNA or RNA from dying cells (for reviews seeMarshak-Rothstein, 2006;Barrat and Coffman, 2008). IFN- and PDCs have been proposed to contribute to the pathogenesis of other autoimmune diseases Desformylflustrabromine HCl characterized by IFN- signature as well. Indeed, type I IFNproducing PDCs accumulate in the pancreas, muscle, and salivary glands of people affected by diabetes mellitus, dermatomyositis, and Sjgrens syndrome, respectively, strongly suggesting that dysregulated PDC activation could be a more general feature of autoimmune disease (for reviews seeUeno et al., 2007;Barrat and Coffman, 2008;Guiducci et al., 2009). PDCs and type I IFN appear to play a similar role in several cutaneous autoimmune diseases, including lichen planus, dermatomyositis, lichen sclerosis, cutaneous graft versus host disease and the cutaneous forms of lupus (cutaneous lupus erythematosus [CLE]; for review seeWenzel and Tting, 2008). The common pathological feature of these Desformylflustrabromine HCl diseases is interface dermatitis, a specific inflammatory pattern characterized by (a) vacuolar changes (liquefaction) of the basal layers of the epidermis, (b) the presence of apoptotic keratinocytes, (c) the accumulation of cytotoxic CD8 T cells and neutrophils in the upper dermis, and (d) prominent IFN- signature in the skin. The close association between IFN-producing PDCs and granzyme Bpositive T cells together with accumulation of nucleic acidcontaining ICs at the junction of dermis and epidermis (for review seeMcCauliffe, 1996) suggests that the chronic presence of PDCs producing IFN- may play a central role in disease development (Blomberg et al., 2001;Farkas et al., 2001; for review seeWenzel and Tting, 2008). Despite this evidence implicating PDCs in autoimmune skin inflammation in humans (for review seeWenzel and Tting, 2008), studies of the mode of activation of PDCs and Desformylflustrabromine HCl their contribution to pathogenesis have been hampered by the absence of an animal model reflecting the central features of such diseases. In this study, we report development of a mouse model in which cutaneous injury Desformylflustrabromine HCl by tape stripping leads to rapid infiltration and activation IGF1 of PDCs and neutrophils. Although tape stripping causes a transient, self-limiting response in normal mice, the same treatment in a strain of lupus-prone mice produces a chronic lesion with many similarities to CLE. Our data thus suggest that when chronically activated, PDCs are a key player in inducing skin damage through sustained production of IFN-regulated genes as well as proinflammatory cytokines. Furthermore, we demonstrate that novel specific inhibitors of TLR7 and TLR9 can prevent skin damage when used in therapeutic settings. == RESULTS == == Activated PDCs and neutrophils infiltrate skin rapidly after tape stripping == As a method to induce slight cutaneous injury and swelling, we used tape stripping, a method previously used to provoke disease in mouse models of psoriasis and atopic dermatitis (Inoue et al., 2005;Sano et al., 2005;Jin et al., 2009). Tape stripping has also.