Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy

Abstract

Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

Keywords: T cell; TCA; biomarkers; glycolysis; keratinocyte; lipid metabolism; metabolic targets; psoriasis.

FIGURE 1

Metabolic derangements in T cells (top) and keratinocytes (bottom) in psoriasis. Metabolic derangements in activated T cells aim to cover their needs in energy and substrates (enhanced glycolysis and downstream energy metabolism pathways, shown in bold). However, T cells residing in the skin (such as memory T cells) rely on the uptake of lipids from the lipid-rich and low-glucose microenvironment. Damaged keratinocytes upregulate glycolytic pathways to cover their proliferative demands as well (shown in bold). Activation of the mammalian target of the rapamycin (mTOR) pathway via the increased amino acid availability and the abundance of pro-inflammatory mediators facilitates the high proliferation and cytokine secretion by activated T cells and keratinocytes. Increased influx of glucose and amino acids is facilitated by the overexpression of the respective transporters on the cell membrane of T cells and keratinocytes (shown in bold). Only primary substrates are shown for each transporter. Gut microbiome deregulation and the aberrant production of microbial metabolites result in intestinal permeability, activation of pro-inflammatory Th-17 cells and suppression of Tregs, while it promotes the disruption of the epidermis integrity. Abbreviations: AA, amino acids; ASCT, neutral amino acid transporter; GLUT1, glucose transporter; LAT, L-type amino acid transporter; mTOR, mammalian target of the rapamycin; OXPHOS, oxidative phosphorylation; SNAT, odium-coupled neutral amino acid transporter; TCA, tricarboxylic acid cycle; Th-17, T-helper 17 cells; Treg, T regulatory cells; TRM, tissue-resident memory cells [Modified from (21)].