Acta Dermato-Venereologica, issue 9 97-9CompleteContent | Page 12

INVESTIGATIVE REPORT Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod- induced Psoriasis in Mice Claudia BUERGER 1# , Nitesh SHIRSATH 2# , Victoria LANG 1 , Sandra DIEHL 1 , Roland KAUFMANN 1 , Andreas WEIGERT 3 , Ying- ying HAN 3 , Christian RINGEL 3 and Peter WOLF 2 1 Department of Dermatology, Venereology and Allergology and 3 Institute of Biochemistry I, Clinic of the Goethe University, Frankfurt, Germany, and 2 Department of Dermatology, Medical University of Graz, Graz, Austria # These authors are both first authors and contributed equally to this work. The mTOR (mechanistic target of rapamycin) inhi- bitor rapamycin has long been known for its immu- ne suppressive properties, but it has shown limited thera peutic success when given systemically to pa- tients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by in- terfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapa- mycin treatment. Immunohistological analysis revea- led that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibi- tion as a novel anti-psoriatic strategy. Key words: psoriasis; imiquimod; rapamycin; mTORC. Accepted Jun 8, 2017; Epub ahead of print Jun 9, 2017 Acta Derm Venereol 2017; 97: 1087–1094. 1087 Corr: Claudia Buerger, Department of Dermatology, Venereology and Al- lergy, Clinic of Goethe-University, Theodor-Stern-Kai 7, DE-60590 Frank- furt am Main, Germany. E-mail: [email protected] and Peter Wolf, Department of Dermatology, Medical University of Graz, Auenbrugger- platz 8, AT-8036 Graz, Austria. E-mail: [email protected] P soriasis is one of the most common inflammatory skin disorders, affecting approximately 3% of the world’s population (1). Several cellular changes in the skin, such as epidermal hyperplasia (acanthosis) and aber- rant differentiation (parakeratosis), along with dermal inflammatory infiltrates related to innate and adaptive immune response and increased tortuous capillaries (angiogenesis) define its severity. This series of events leads to formation of sharply demarcated, red scaly erythematous plaques on the skin, which can be itchy and painful (2). Psoriasis is heterogeneous in nature and exists in several distinct forms, in which approximately 80% of cases are classified as mild (defined by a Psoriasis Area Severity Index (PASI) ≤ 10) and in which the extent of body surface area covered varies widely from patient to patient (1). The severity of the disease usually determines the therapeutic approach to controlling psoriasis. Ap- proximately 70–80% of all patients with psoriasis who have mild disease can be treated adequately with topical therapies, using agents such as corticosteroids, vitamin D analogues, topical retinoids and calcineurin inhibitors. For moderate-to-severe psoriasis (e.g. affecting large surface areas) a well-established treatment regimen is a combination of topical agents and phototherapy or sys- temic drugs (3, 4). In recent years no novel substances have been developed for topical treatment, and newly introduced agents have mainly been analogues, deriva- tives or new formulations of already known agents (5). PI3-kinase (PI3-K) and its downstream effector, mTORC1, being fundamental components of immune cell-signalling networks, play a crucial role in skin homeostasis and morphogenesis, especially in the re- gulation of keratinocyte differentiation and epidermal stratification (6–8). We have shown previously that the mTOR kinase itself and its downstream target, ribosomal protein S6, are hyper-activated in psoriatic lesions (9, 10). In addition, the PI3-K/mTOR pathway is thought to play a role in Th1-Th2-Th17 imbalance in the pathogenesis of psoriasis (11). The mTOR inhibitor rapamycin, also known as sirolimus, was initially investigated as an antifungal agent and was used for its immunosuppres- sant properties (12) and also showed anti-tumourigenic potential. Rapamycin binds to the cytoplasmic protein FKPB-12, which interacts with mTORC1, thus blocking the mTOR target proteins S6 and 4E-BP that are essential for protein synthesis and thereby for cell growth and proliferation (13). The aberrant activation of mTOR in different cancers and in epidermal tumours has promoted the investigation of rapamycin as an anti-tumourigenic therapy and enabled further development of a range of small molecule inhibitors that may prove effective in disease control (14). There have not been many large-scale trials to validate the potential of rapamycin as an effective topical anti- inflammatory agent in psoriasis (15), and few studies have tested its anti-psoriatic effect after oral administra- tion (16–18). However, topical rapamycin treatment for tuberous sclerosis complex (TSC) is well documented. In TSC, genetic mutations of the TSC1 or TSC2 gene inhibit the association of their protein products, tuberin and hamartin, leading to an aberrant upregulation of the mTOR signalling pathway. Reportedly, topical rapamy- This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340/00015555-2724 Acta Derm Venereol 2017; 97: 1087–1094