The role of hypoxia and metabolism in the pathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a rare autoimmune disease with heterogeneous symptoms and characterized by immune alteration, vascular abnormalities, fibrosis and hypoxia. SSc is a poorly understood disease with no available effective cure and an unknown pathophysiology. Recent studies identified chemokine (C-X-C-motif) ligand-4 (CXCL4) as a potential biomarker produced by pro-inflammatory immune-cells. Besides, alteration in fat metabolism has been shown to elicit immune-cell polarisation in SSc. The aim of this thesis is to explore the augmented production of CXCL4 and its role in aberrant fibrogenesis in patients with SSc. Moreover, the metabolic status of fat biology in pathophysiology of SSc was further inquired. In healthy immune-cells CXCL4-production depends on mitochondrial reactive oxygen species and hypoxia inducible factor (HIF)-2 stabilization. We observed that Toll-Like receptor (TLR) triggered upon hypoxic environment is responsible for augmented CXCL4-production in SSc. Also, we pinpointed the potential beneficial role of HIF-2 stabilization on cytokine production and confirmed its potential features as a therapeutic target in SSc treatment. Besides, we demonstrated that fatty acids and carnitine composition were altered in SSc and demonstrated that inhibiting fatty acid oxidation abates pro-inflammatory cytokine production in immune-cells of SSc patients. Finally, we observed that inhibition of mammalian target of rapamycin (mTOR), with metformin reduces pro-inflammatory cytokine production, signifying the potential therapeutic effect of metabolic mediators in immune cells. Taken together, targeting TLR stimulation, HIF-2 stabilization and fatty acid oxidation inhibits aberrant cytokine and CXCL4-production in immune cells and metformin treatment can contribute in reducing pro-inflammatory cytokine production in patients with SSc.