Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis

Abstract

Introduction: The modulation of immunometabolic pathways is emerging as a promising therapeutic target for immune-mediated diseases. However, the immunometabolic features of psoriatic disease and the potential targets for immunometabolic intervention in the different T-cell subsets involved in its pathogenesis remain unclear.

Methods: In this study, we analyzed circulating blood single-cell data from healthy controls (HC), psoriasis (PSO), and psoriatic arthritis (PSA) patients, and revealed their metabolic features of T-cell subsets: CD4+ central memory T cells (TCMs), CD8+ effective memory T cells (TEMs), regulatory T cells (Tregs), mucosal-associated invariant T cells (MAITs ), and γδ T cells. Pearson test was performed to determine the linkages between differential metabolic and inflammatory pathways. Based on these results, we also analyzed the potential impacts of biological antibodies on differential metabolic pathways by comparing the immunometabolism differences between PSA patients without and with biological treatment.

Results: Our results suggest that upregulation of ascorbate and aldarate metabolism, as well as fatty acid degradation, may enhance the immune suppression of Tregs. Enhanced metabolism of alpha-linolenic acid, linoleic acid, and arachidonic acid may inhibit the pro-inflammatory functions of CD4+ TCMs and CD8+ TEMs in PSO and PSA, and protect the immune suppression of Tregs in PSA. We propose that supporting ascorbic acid and fatty acid metabolic pathways may be an adjunctive reprogramming strategy with adalimumab and etanercept therapy.

Discussion: These findings not only provide insights into immunometabolism characteristics of psoriatic disease, but also offer preliminary options for the auxiliary treatment of psoriasis.

Keywords: TCM; TEM; Treg; immunometabolism; psoriasis; psoriatic arthritis; single-cell transcriptomics.

Figure 1

Visualization and proportion of T-cell subsets in group HC, PSO, PSA, PSA_SM. (A) tSNE shows the dimensional reduction of T-cell subsets. (B, C) Fraction distribution of T-cell subsets in group HC, PSO, PSA, PSA_SM. (D) Fraction distribution of T-cell subsets in specific systemic medication groups.

Figure 2

GSVA (HALLMARK) analysis for immunometabolic patterns of T-cell clusters in HC (A), PSO (B), and PSA (C). The focused metabolic gene sets are highlighted in red, and the cycle-related gene sets are highlighted in blue. (D) Patterns of fatty acid metabolism and glycolysis gene sets performed among T-cell subsets of group HC, PSO, and PSA based on GSVA scores.

Figure 3

Determining immunometabolic pathways in T-cell subsets of PSO. (A, B) Fraction and number of CLA+ and CLA- subfractions. (C) The gene expression value of SELPLG showed only a weakly-expressed peak in each focused subset of PSO. (D) Metabolic difference landscape of focused subsets between PSO and HC at the levels of Cluster and CLA+ by GSEA. Gray background indicates a negative normalized enrichment score (NES), and the bright background indicates a positive NES. The NES reflects the degree to which a gene set is downregulated (negative NES) or upregulated (positive NES). The area of the dot corresponds to the NES absolute value. The color of the dots corresponds to the P value. (E) GSEA showed an obvious increase of ascorbate and aldarate metabolism in Tregs of PSO. Immunometabolic linkage between metabolic pathways of α-linolenic acid metabolism, linoleic acid metabolism, arachidonic acid metabolism, ascorbate and aldarate metabolism, or fatty acid degradation and immune events in CD4+ TCMs (F), CD8+ TEMs (G), and Tregs (H) of PSO at the level of Cluster.

Figure 4

Determining immunometabolic pathways in T cells of PSA. (A, B) Fraction and number of CXCR3+ and CXCR3- subfractions. (C) The gene expression value of CXCR3 showed loss of high-expressed peak in each focused subsets of PSA. (D) Metabolic difference landscape of focused subsets between PSA and HC at the levels of Cluster and CXCR3+ by GSEA. Gray background indicates a negative normalized enrichment score (NES) and the bright background indicates a positive NES. The NES reflects the degree to which a gene set is downregulated (negative NES) or upregulated (positive NES). The area of the dot corresponds to the NES absolute value. The color of the dots corresponds to the P value. (E) GSEA showed an obvious increase of ascorbate and aldarate metabolism in Tregs of PSA. Immunometabolic linkage between metabolic pathways of α-linolenic acid metabolism, linoleic acid metabolism, arachidonic acid metabolism, ascorbate and aldarate metabolism, or fatty acid degradation and immune events in CD4+ TCMs (F), CD8+ TEMs (G) and Tregs (H) of PSA at the level of Cluster.

Figure 5

The alterations of candidate immunometabolic pathways in T-cell subsets with systemic medications (PSA_SM).