A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus
Introduction
Psoriasis (PSO) is one of the most common inflammatory skin diseases, and is found in approximately 1–3% of the world general population [1]. For a long time, PSO had been considered as a non-pruritic dermatitis. However, more recently, a number of studies have demonstrated that approximately 60–90% of patients with PSO suffer from pruritus [1], [2], [3], [4], [5], [6]. Although psoriatic patients consider pruritus as the most bothersome subjective sensation [5], [7], effective therapy for pruritus in PSO has not been established.
CD26 is a 110 kDa surface glycoprotein with dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) activity as a serine protease that cleaves dipeptides from the N-terminus of peptides at the penultimate position [8], [9], [10]. CD26 is also associated with T cell signal transduction processes as a costimulatory molecule, as well as being a marker of T cell activation [11], [12]. We have previously reported that CD26-mediated costimulatory activity is exerted via its DPPIV enzyme activity [13]. More recently, we have shown that serum soluble CD26 (sCD26) and DPPIV enzyme activity (sDPPIV) are inversely correlated with disease activity in patients with systemic lupus erythematosus [14]. In addition, sCD26 and sDPPIV are involved in the pathogenesis of various cancers including colorectal cancer, hepatocellular carcinoma, prostate cancer and malignant mesothelioma [15], [16], [17], [18], [19]. Other investigators have reported that CD26/DPPIV was upregulated in psoriatic skin and that DPPIV inhibitor ameliorated psoriasis [20], [21], [22], [23], although the biological role of CD26/DPPIV in PSO has not yet been elucidated. Meanwhile, DPPIV enzyme activity has been widely studied in metabolic and endocrine disorders, and DPPIV inhibitors have been developed as a new class of anti-diabetic drugs which act by inhibiting DPPIV, the enzyme that inactivates incretin hormone [24], [25], [26]. The potentially important role played by CD26/DPPIV in the clinical setting has led to rising interest in serum sCD26 level and sDPPIV enzyme activity in various human conditions over the past decade.
Substance P (SP) is a neuropeptide involved in afferent neuronal signal transduction [27], [28]. Activation of sensory neurons in the skin causes the release of SP [29], [30]. Once released, SP binds to neurokinin receptors including neurokinin-1 receptor (NK-1R) found on keratinocytes and cutaneous nerve endings, resulting in the release of additional itch mediators [29], [31]. Substance P therefore appears to act to induce itch. It has been reported that the number of SP-containing nerves in the perivascular areas of pruritic psoriatic skin was increased and that expression of SP receptor in epidermis from pruritic psoriatic subjects was upregulated [3], [32]. On the other hand, SP consists of 11 amino acids residues and contains the DPPIV-target sequence at its N-terminal position [33]. Previous report utilizing DPPIV deficient rat showed that circulating SP was metabolized by DPPIV enzyme [34]. However, it is not clear whether degradation of SP by DPPIV enzyme affects pruritus in patients with PSO.
In the present study, utilizing clinical serum samples of PSO patients and in vivo experimental pruritus models, we evaluated for a potential association between DPPIV and an increased risk for SP-induced pruritus, and attempted to identify possible underlying treatment targets in pruritus of PSO. We showed that levels of DPPIV enzyme activity in sera of patients with PSO were significantly increased compared to those of healthy controls. Moreover, truncated form SP cleaved by DPPIV was significantly increased in sera of PSO. In an in vivo pruritus model induced by full-length SP, scratching was decreased by treatment with a DPPIV inhibitor. Moreover, scratching was increased following injection of truncated form SP. Furthermore, DPPIV-knockout (CD26KO) mice showed attenuation of scratching induced by SP. Finally, scratching was decreased following the administration of a DPPIV inhibitor in an imiquimod (IMQ)-induced PSO model. On the other hand, scratching induced by IMQ was increased in DPPIV overexpressing transgenic (DPPIV-Tg) mice. These results suggest that inhibition of DPPIV enzyme activity regulates pruritus in PSO.
Section snippets
Patients and serum collections and storage
The base cohort consisted of all PSO patients regularly seen and treated at the Juntendo Urayasu Hospital between May 2013 and October 2014. Peripheral blood samples were collected from 48 PSO patients and 18 healthy adult volunteers, using BD Vacutainer blood collection tube SSTII (BD, Franklin Lakes, NJ). Serum was obtained from 5 mL whole blood by centrifugation at 1500 × g at 4 °C for 10 min, and stored at −80 °C in 500 μL aliquots. Human study protocols were approved by the Ethics Committees at
Serum levels of sCD26 and sDPPIV enzyme are increased in patients with PSO
To determine whether sCD26 and sDPPIV enzyme play a role in PSO, we first evaluated levels of sCD26 and sDPPIV enzyme activity in sera of patients with PSO. For this purpose, peripheral blood samples were collected from healthy adult volunteers and PSO patients (regularly seen and treated at the Juntendo Urayasu Hospital). Of the 48 patients, mean (years ± S.D.) age was 49.9 (±16.9), male/female was 41/7. No patients with diabetes mellitus, hepatic or renal dysfunction were included in PSO cohort
Discussion
In the present study, we demonstrated that serum levels of DPPIV enzyme activity was significantly increased in patients with PSO, concomitant with elevation of truncated form of SP. Moreover, overexpression of DPPIV enzyme activity exaggerated itch scratching behavior in psoriatic pruritus murine model induced by IMQ cream. Furthermore, treatment with the DPPIV inhibitor sitagliptin improved itch scratching behavior in murine pruritus models induced by SP administration or IMQ cream.
Pruritus
Conflicts-of-interest disclosure
The authors have no conflict of interest to declare.
Funding sources
This work was supported by a Grant-in-Aid (S1311011) from the Foundation of Strategic Research Projects in Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; JSPS KAKENHI Grant Number 15H04879; JSPS KAKENHI Grant Number 15K15324; JSPS KAKENHI Grant Number 16H05345; JSPS KAKENHI Grant Number 26830114; a grant of the Ministry of Health, Labour, and Welfare, Japan (Grant Number 150401-01).
Acknowledgements
The authors thank Dr. Airi Jo-Watanabe (Department of Biochemistry, Juntendo University School of Medicine), Dr. Hyeon-cheol Lee (Department of Biochemistry, Juntendo University School of Medicine), Mr. Nobuaki Takahashi (Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of medicine), Mrs. Hiroko Madokoro (Department of Pathology, Keio University School of Medicine) and Mrs. Yuka Narita (Department of Therapy Development and Innovation for Immune
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