Metabolic dynamics in psoriatic epidermis: Enhanced glucose and lactate uptake, glycolytic pathway and TCA cycle dynamics

Psoriasis, a prevalent chronic inflammatory skin disorder, impacts approximately 2%–3% of the global population.1 This disease is marked by an expedited proliferation of keratinocytes and a significantly shortened turnover time. Additionally, a notable association exists between psoriasis and metabolic syndrome, with a considerable portion of patients displaying obesity. Prior research has underscored the importance of glucose uptake in the proliferation of keratinocytes.2 Conversely, the tricarboxylic acid (TCA) cycle are crucial for the differentiation of these cells.3 In the context of psoriasis, an increase in GLUT1 expression has been observed, correlating with heightened severity scores, suggesting an enhanced glycolytic activity.2 The glycolytic pathway facilitates the conversion of glucose into ATP and lactate, the latter of which is either expelled from the cell via MCT4 or reabsorbed through MCT1.4 Once inside the cell, lactate contributes to ATP production through the TCA cycle. An in-depth understanding of the alterations and dynamics within these metabolic pathways, including glycolysis, the TCA cycle and lactate transport, is essential for a comprehensive grasp of the pathophysiology of psoriasis. However, the precise mechanisms through which lactate is metabolized in psoriatic keratinocytes remain unclear, highlighting a significant gap in our understanding of the disease's metabolic foundations. To delve deeper into the metabolic processes in keratinocytes of psoriasis vulgaris at a single-cell resolution, we re-analysed publicly available single-cell RNA sequencing data from prior psoriasis studies (GSE162183),5 focusing specifically on epidermal keratinocytes (Figure S1a,b). We discovered significant gene expression differences between healthy individuals and psoriasis patients in both undifferentiated and differentiated epidermal keratinocytes (Figure S1a). Analysis of gene expression profiles in these cells revealed a marked upregulation of glucose transporter genes (e.g. SLC2A1) and cell proliferation markers (e.g. MKI67) in the undifferentiated keratinocytes of psoriatic lesions (Figure S1c). Additionally, the expression of inflammatory markers, such as KRT16 and S100A7, was significantly elevated in the differentiated keratinocytes within the psoriatic epidermis. Subsequent pathway analysis of the upregulated genes in each cell type indicated an elevation of genes related to cell proliferation in psoriatic undifferentiated keratinocytes, while genes associated with aerobic respiration were upregulated in both undifferentiated and differentiated keratinocytes (Figure 1A). Further investigation into the gene expression related to representative metabolic pathways, specifically glycolysis and the TCA cycle, in these keratinocytes revealed an upregulation in psoriasis patients, indicating a metabolic shift towards these pathways (Figure 1B). This prompted a closer examination of the glucose transporter SLC2A1 and the lactate transporter SLC16A1, both of which are highly expressed in keratinocytes. The elevated expression of the glucose transporter SLC2A1 was particularly evident in undifferentiated keratinocytes from psoriasis patients (Figure 1C). Additionally, SLC16A1, a transporter involved in lactate uptake, showed increased levels in psoriatic undifferentiated keratinocytes. Immunohistochemistry findings corroborated the upregulated expression of GLUT1 (SLC2A1) in psoriatic undifferentiated keratinocytes and highlighted elevated MCT1 (SLC16A1) expression in both undifferentiated keratinocytes from psoriasis patients and differentiated keratinocytes from both cohorts, with consistent expression of MCT4 (SLC16A3) observed in healthy and psoriatic differentiated keratinocytes (Figure 1D, Figure S1d). These results suggest a regulatory mechanism involving the upregulation of GLUT1 and MCT1 in undifferentiated keratinocytes of psoriasis patients, facilitating increased glucose uptake for glycolysis and lactate uptake for TCA cycle activation. In contrast, differentiated keratinocytes in psoriasis exhibit fewer metabolic alterations compared to their undifferentiated counterparts. In normal skin, cell proliferation is mediated by the glycolysis in undifferentiated keratinocytes, while cell differentiation in differentiated keratinocytes is driven by the TCA cycle. The enhancement of the glycolytic system in keratinocytes, driven by increased proliferation, coupled with the activation of the TCA cycle through lactate uptake, suggests a complex metabolic reprogramming in psoriasis (Figure 1E). Although the current data are derived solely from single-cell RNA sequencing and immunostaining, they provide new insights into the metabolic alterations in keratinocyte metabolism in psoriasis, underlining the necessity for further studies using in vitro and in vivo models to fully elucidate these mechanisms. Satoshi Nakamizo: Conceptualization; methodology; software; validation; formal analysis; investigation; data curation; writing—original draft; visualization. Hiromi Doi: Methodology; formal analysis; investigation; data curation; writing—review and editing. Kenji Kabashima: Writing—review and editing; supervision; project administration; funding acquisition. This work was supported by the Japan Society for the Promotion of Science KAKENHI (20H05697) and AMED-CREST (JP20gm1210006). No conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Annotation of psoriatic keratinocytes by re-analysis of single-cell RNA sequencing. Data S1. Supplemental Material and Method. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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