Abstract
Psoriasis is a chronic skin disorder associated with multiple sequelae, such as psoriatic arthritis and cardiovascular diseases. Increasing evidence has shown that γδ T cells, as sources of IL-17A, play critical roles in psoriatic inflammations. However, there still lack effective ways to manipulate these pathogenic γδ T cells, which are less well studied than αβ T cells. The present study aims to characterize the phenotype of γδ T cells and evaluate the impact of D-mannose (a C-2 epimer of glucose) on γδ T cell-mediated psoriasis. We found that skin-draining LN γδ T cells underwent robust proliferation and acquired an IL-17-producing phenotype during psoriasis. The transcriptomic profiles of these psoriatic γδ T cells had elevated glycolytic signatures. Importantly, D-mannose treatment suppressed the γδ T cell reaction and successfully alleviated the local and systematic inflammation induced by imiquimod. The decreased AKT/mTOR/HIF-1α signaling and glycolytic ability may contribute to the suppression of γδ T cells achieved by D-mannose. Our study increased understanding of γδ T cells in psoriasis and promoted D-mannose utilization as a potential clinical application for autoimmune diseases driven by γδ T cells.
Highlights
Psoriasis is a persistent immune-mediated inflammatory skin disorder affecting 2-3% of the population worldwide [1–3]
We determined that D-mannose, a hexose sugar, could alleviate the experimental psoriasis by suppressing gd T cells via inhibition of glycolysis and AKT/mTOR/HIF1a signaling
In accordance with previous reports [16, 18], our study found that the gd T cells from draining lymph node (DLN) of IMQ-treated mice had augmented proliferation compared with healthy controls
Summary
Psoriasis is a persistent immune-mediated inflammatory skin disorder affecting 2-3% of the population worldwide [1–3]. TCRab+ Th cells have received plentiful attentions, but increasing evidences have shown that IL-17-secreting TCRgd+ (gd17) T cells are pivotal mediators in psoriasis [13–15] In both IL-23-induced and imiquimod (IMQ)-induced models, gd T cell deletion rather than ab T cell deletion alleviated skin inflammations [16]. Recent works have shown that D-mannose can impair glycolysis and promote fatty acid oxidation in T cells [29] It can induce regulatory T cells (Tregs) and alleviate the immunopathology of diabetes, airway inflammation and lupus [28–30]. The suppression of succinate-mediated HIF-1a activation was reported in macrophages treated with D-mannose [31]. In addition to intensive activation and proliferation, we found that gd T cells from the skin DLN of psoriatic mice had a higher level of p-HIF-1a expression and upregulated genes associated with glycolysis. We speculated that the decreased AKT/mTOR/HIF-1a signaling and glycolytic ability in gd T cells may contribute to the suppression of psoriasis achieved by D-mannose
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