Unraveling the immunometabolism puzzle: Deciphering systemic sclerosis pathogenesis

Abstract

The article delves into the pathogenesis of systemic sclerosis (SSc) with an emphasis on immunometabolism dysfunctions. SSc is a complex autoimmune connective tissue disorder with skin and organ fibrosis manifestation, vasculopathy, and immune dysregulation. A growing amount of research indicates that immunometabolism plays a significant role in the pathogenesis of autoimmune diseases, including SSc. The review explores the intricate interplay between immune dysfunction and metabolic alterations, focusing on the metabolism of glucose, lipids, amino acids, the TCA (tricarboxylic acid) cycle, and oxidative stress in SSc disease. According to recent research, there are changes in various metabolic pathways that could trigger or perpetuate the SSc disease. Glycolysis and TCA pathways play a pivotal role in SSc pathogenesis through inducing fibrosis. Dysregulated fatty acid β-oxidation (FAO) and consequent lipid metabolism result in dysregulated extracellular matrix (ECM) breakdown and fibrosis induction. The altered metabolism of amino acids can significantly be involved in SSc pathogenesis through various mechanisms. Reactive oxygen species (ROS) production has a crucial role in tissue damage in SSc patients. Indeed, immunometabolism involvement in SSc is highlighted, which offers potential therapeutic avenues. The article underscores the need for comprehensive studies to unravel the multifaceted mechanisms driving SSc pathogenesis and progression.

Keywords: Fibrosis; Immunometabolism; Systemic sclerosis; Treatment.

Fig. 1

Interplay of endothelial activation and immunometabolic pathways in systemic sclerosis: Activated endothelial cells lining the blood vessels become leaky, facilitating the infiltration of immune cells into healthy tissues. Immune cell activation is initiated by damage-associated molecular patterns (DAMPs) released by stressed/damaged cells. DAMPs bind to Toll-like receptors (TLRs) on immune cells, further fueling inflammation and even influencing their metabolic state. Immune cells, including T cells, B cells, and macrophages, become activated and undergo metabolic reprogramming, switching to a more energetically active state to fuel their aggressive inflammatory response. The target of this immune attack are fibroblasts, the cell type responsible for tissue repair. However, in systemic sclerosis, these fibroblasts become hyperactivated and transition to a profibrotic state, characterized by excessive collagen production, the main building block of scar tissue. This relentless collagen deposition ultimately leads to the fibrosis that disrupts organ function and causes the debilitating symptoms of systemic sclerosis.

Fig. 2

Dysregulated metabolic pathways in SSc: As depicted in the figure, various metabolic pathways are dysregulated in SSc patients. Impaired metabolic pathways, including glycolysis, TCA cycle, beta-oxidation, lipid synthesis, and ROS production led to production of high levels of some intermediate molecules. Excessive amount of these molecules could affect cell fate, which is generally associated with aggressive phenotype and inflammatory state of these cells. Chronic inflammatory state due to metabolic disturbance is associated with fibrosis induction, an important clinical presentation of SSc patients. Finally, this picture depicts the dysregulated metabolic pathways that are associated with SSc pathogenesis.