Acta Dermato-Venereologica 99-2CompleteContent | Page 17

196 INVESTIGATIVE REPORT The Keratinocyte Transcriptome in Psoriasis: Pathways Related to Immune Responses, Cell Cycle and Keratinization Lorenzo PASQUALI 1 , Ankit SRIVASTAVA 1 , Florian MEISGEN 1 , Kunal DAS MAHAPATRA 1 , Ping XIA 1,3 , Ning XU LANDÉN 1 , Andor PIVARCSI 1 and Enikö SONKOLY 1,2 Dermatology and Venereology Section, Department of Medicine Solna, Karolinska Institutet, 2 Dermatology Unit, Karolinska University Hospital, Stockholm, Sweden, and 3 Dermatology Unit, Wuhan No.1 Hospital, Wuhan, China 1 Psoriasis is a common immune-mediated disease re- sulting from altered cross-talk between keratinocy- tes and immune cells. Previous transcriptomic studies have identified thousands of deregulated genes in pso- riasis skin; however, the transcriptomic changes con- fined to the epidermal compartment remained poorly characterized. The aim of this study was to characte- rize the transcriptomic landscape of psoriatic kerati- nocytes, using sorted CD45 neg epidermal cells. Genes with functions in innate immunity, type I interferon response, cell cycle and keratinization were enriched among deregulated genes in psoriatic keratinocytes. Gene set enrichment analysis indicated the dominance of interleukin (IL)-22/IL-17A signatures in the epider- mal psoriasis-signature. A set of deregulated genes overlapped with psoriasis-associated genetic regions, suggesting that genetic variations affecting gene ex- pression in keratinocytes contribute to susceptibility to psoriasis. Several psoriasis-susceptibility genes, which were previously believed to be expressed prefe- rentially or exclusively in immune cells, were identified as having altered expression in psoriatic keratinocy- tes. These results highlight the role of keratinocytes in the pathogenesis of psoriasis, and indicate that both genetic factors and an inflammatory microenvironme- nt contribute to epidermal alterations in psoriasis. Key words: psoriasis; keratinocyte; transcriptome; cytokine; epidermis. Accepted Oct 15, 2018; E-published Oct 15, 2018 Acta Derm Venereol 2019; 99: 196–205. Corr: Enikö Sonkoly, Dermatology and Venereology Section, Department of Medicine Solna, Karolinska Institutet, CMM L8:02, SE-171 76 Stock- holm, Sweden. E-mail: [email protected] P soriasis is a common chronic inflammatory skin disease that affects > 125 million people worldwide (1). It is a multifactorial disease (2), with both genetic and environmental factors contributing to its develop- ment. Genome-wide association studies have identified more than 40 psoriasis-associated single-nucleotide polymorphisms (SNPs) (3) located near to genes linked to innate and adaptive immunity as well as keratinocyte differentiation (4). The characteristic skin lesions in psoriasis are ery­ thematous scaly plaques, characterized by epidermal hyperplasia and epidermal and dermal infiltration of im- doi: 10.2340/00015555-3066 Acta Derm Venereol 2019; 99: 196–205 SIGNIFICANCE Psoriasis is a common inflammatory skin disease resulting from an interplay of skin cells (keratinocytes) and immune cells. While more than 1,000 genes have altered expression in psoriasis skin, the contribution of keratinocytes to these changes is poorly characterized. This study found that ke- ratinocytes from psoriasis skin display marked changes in gene expression, associated with proliferation, differentia- tion and genes induced by inflammatory mediators. Part of the identified genes overlap with genetic regions associa- ted with susceptibility to psoriasis. These results suggest that keratinocytes in psoriasis have both intrinsic (genetic) and extrinsic (inflammation-induced) changes, and high- light the role of keratinocytes in psoriasis. mune cells (2). Psoriatic skin inflammation is thought to develop as a result of abnormal communication between infiltrating immune cells and activated keratinocytes. Th17 cells and their secreted cytokines, interleukin (IL)-17, and IL-22, in synergy with interferon (IFN)-γ and tumour necrosis factor alpha (TNF-α), have been identified as central players in the pathogenesis (2, 5). Keratinocytes, which were previously thought of as passive bystanders in the inflammatory process, play an active role both in the initiation and maintenance of psoriatic skin inflammation, by secreting chemokines, cytokines, and antimicrobial peptides, which lead to further chemoattraction and activation of immune cells in the skin, amplifying the inflammatory process (5). Moreover, psoriatic keratinocytes follow an altered differentiation programme and have an increased pro- liferation rate. Previous transcriptomic studies on full-depth skin biopsies have demonstrated profoundly altered gene ex- pression in psoriasis plaques, with thousands of differen- tially expressed genes (DEGs) (6) compared with healthy skin. Gene expression changes, although with a lower number of DEGs, have been detected even in the non- lesional, healthy-looking skin of patients with psoriasis, suggesting a “pre-psoriatic” state of non-lesional skin. However, most transcriptomic studies in psoriasis have utilized full-depth skin biopsies (6–9). Although several attempts have been made to characterize transcriptomic changes confined to keratinocytes, the contribution of the epidermal compartment to the total changes in psoriasis This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.