Reputation of endogenous DNA and RNA by cells expressing TLR7 and TLR9 is an important contributor to the pathogenesis of systemic lupus erythematosus and has been suggested to contribute to cutaneous lupus and to a group of related inflammatory skin diseases termed interface dermatitis. of chronic lesions characterized by a persistent type I IFN gene signature and many clinical and histological features of cutaneous lupus. Depletion of PDCs before injury prevented 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 Berberine HCl 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 self-nucleic acids is usually 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 see Berberine HCl Marshak-Rothstein 2006 Barrat and Coffman 2008 IFN-α and Berberine HCl PDCs have been proposed to contribute to the pathogenesis of other autoimmune diseases characterized by IFN-α signature as Berberine HCl well. Indeed type I IFN-producing PDCs accumulate in the pancreas muscle and salivary glands of people PCDH9 affected by diabetes mellitus dermatomyositis and Sj?gren’s syndrome respectively strongly suggesting that dysregulated PDC activation could be a more general feature of autoimmune disease (for reviews see Ueno 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 see Wenzel and Tüting 2008 The common pathological feature of these 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-α signature in the skin. The close association between IFN-α-creating PDCs and granzyme B-positive T cells as well as deposition of nucleic acid-containing ICs on the junction of dermis and epidermis (for examine discover McCauliffe 1996 shows that the persistent existence of PDCs creating IFN-α may enjoy a central function in disease advancement (Blomberg et al. 2001 Farkas et al. 2001 for review discover Wenzel and Tüting 2008 Not surprisingly proof implicating PDCs in autoimmune epidermis inflammation in human beings (for review discover Wenzel and Tüting 2008 research of the setting of activation of PDCs and their contribution to pathogenesis have already been hampered with the lack of an pet model reflecting the central top features of such illnesses. In this research we report advancement of a mouse model where cutaneous damage by tape stripping qualified prospects to fast infiltration and activation of PDCs and neutrophils. Although tape stripping causes a transient self-limiting response in regular mice the same treatment within 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 moderate cutaneous injury and inflammation 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 been used as a noninvasive method for detecting and diagnosing lupus as lupus patients overreact to this mild cutaneous.