Acta Dermato-Venereologica 99-6CompleteContent | Page 16

INVESTIGATIVE REPORT 579 Aberrant Expression of Histamine-independent Pruritogenic Mediators in Keratinocytes may be Involved in the Pathogenesis of Prurigo Nodularis Weilong ZHONG 1,2 , Xia WU 2 , Wei ZHANG 3 , Jie ZHANG 1 , Xiaofan CHEN 3 , Shihong CHEN 1 , Haiyan HUANG 2 , Yong YANG 1# , Bo YU 2,3# and Xia DOU 2# Department of Dermatology, Peking University First Hospital, Beijing, 2 Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, and 3 Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University, The Hongkong University of Science and Technology Medical Center, Shenzhen, Guangdong, China # These authors contributed equally to this work and should be considered joint corresponding authors. 1 Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with unknown pathogenesis. Many pruritogenic mediators, including nerve growth factor, interleukin (IL)-31, thymic stromal lymphopoietin, and endothelin-1, are implicated in chronic itch and inflammation. This study investigated the mRNA le- vels and immunoreactivity of the nerve growth factor, IL-31, thymic stromal lymphopoietin, and endothelin axes in both lesional and perilesional skin in prurigo nodularis by using quantitative real-time PCR and im- munohistochemistry studies. The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neu- rotrophin receptor was downregulated in prurigo no- dularis lesions. Downregulated expression of IL-31/ IL-31 receptor A and endothelin-3/endothelin recep- tor B and upregulation of thymic stromal lymphopoie- tin receptor were found in prurigo nodularis lesions. Aberrant expression of nerve growth factor, IL-31, en- dothelin, and thymic stromal lymphopoietin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis. Key words: prurigo nodularis; keratinocyte; itch; pruritogenic mediator; nerve growth factor. Accepted Feb 26, 2019; E-published Feb 27, 2019 Acta Derm Venereol 2019; 99: 579–586. Corr: Xia Dou, MD and Bo Yu, MD, Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, China. E-mails: [email protected]; [email protected], and Yong Yang, MD, Department of Dermatology, Peking University First Hospital, Beijing 100034, China. E-mail: [email protected]. P rurigo nodularis (PN) is a chronic skin disorder cha- racterized by symmetrically distributed, highly pruri- tic and hyperkeratotic nodules (1, 2). Recently, PN was defined as a subtype of chronic prurigo that occurs due to neuronal sensitization to itch and the development of an itch-scratch cycle (3). It has been determined that PN has a heterogeneous origin, arising from dermatological (e.g., atopic dermatitis), systemic (e.g., chronic kidney failure) and neurological (e.g., brachioradial pruritus) or psychiatric diseases. However, it usually results from a combination of these different conditions or even from an SIGNIFICANCE · Prurigo nodularis is a highly pruritic and hyperplastic chronic dermatosis with studies mainly focusing on cuta- neous nerve fibres and neuropeptides. · In this study, aberrant expression of nerve growth fac- tor, interleukin-31, thymic stromal lymphopoietin, and endothelin axes was found in prurigo nodularis lesions, especially in the epidermis, indicating the importance of keratinocytes in prurigo nodularis pathogenesis. · The nerve growth factor high-affinity receptor tyrosine kinase receptor A was upregulated while the low affinity receptor p75 neurotrophin receptor was downregulated in prurigo nodularis lesions, suggesting the importance of receptor imbalance in prurigo nodularis pathogenesis. · These pruritogenic mediators may act as biomarkers for anti-pruritic and anti-inflammatory therapies of prurigo nodularis and need further studies. unknown origin. Several reports have shown that many patients with PN show a predisposition to atopy (2, 4, 5). However, the pathogenesis of PN remains unclear, leading to limited effective treatment options (1). The histopathological characteristics of PN are epider- mal hyperplasia, inflammation and neurohyperplasia in the dermis, which suggests that complex interactions bet- ween keratinocytes, immune cells, and sensory neurons might occur and affect the formation and chronicity of PN. Keratinocytes might release chemokines/cytokines that modulate immune cell activity and vice versa. Both kera- tinocytes and immune cells can also produce pruritogens, algogens, and antinociceptive factors that act on sensory neurons, whereas sensory neurons release neuropeptides that target both keratinocytes and immune cells (6, 7). To date, various pruritogenic molecules are implica- ted as mediators of chronic itch and inflammation, such as nerve growth factor (NGF), interleukin-31 (IL-31), thymic stromal lymphopoietin (TSLP), and endothelin-1 (ET-1) (6–8). Interestingly, these mediators can be produ- ced by keratinocytes, thus suggesting that keratinocytes may play an important role in the pathogenesis of PN. However, studies of PN mainly focus on cutaneous nerve fibres and neuropeptides, with relatively scant attention to keratinocytes (1, 9). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3150 Acta Derm Venereol 2019; 99: 579–586