Jun 10: Pathophysiology of systemic sclerosis further elucidated
In his PhD research, Andrea Ottria explored the augmented production of CXCL4 and its role in aberrant fibrogenesis in patients with Systemic sclerosis (SSc). Moreover, the metabolic status of fat biology in pathophysiology of SSc was further inquired. Ottria found several mechanisms thought to be responsible for reduction of pro-inflammatory cytokine production in patients with SSc.
In healthy immune-cells CXCL4-production depends on mitochondrial reactive oxygen species and hypoxia inducible factor (HIF)-2α 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-2α 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-2α 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.
Rare autoimmune disease
Systemic sclerosis (SSc) is a rare autoimmune disease with heterogeneous symptoms and characterized by immune changes, vascular abnormalities, fibrosis and hypoxia. SSc is a poorly understood disease with no available effective cure and an unknown pathophysiology. The disease is diagnosed usually between ages 30 and 60 years, with an incidence ranging from 7-44 cases per 100.000 per year and a female preponderance. Recent studies identified chemokine (C-XC-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 polarization in SSc.
PhD defense
Andrea Ottria (1987, Genova, Italy) obtained his PhD degree on June 10, 2020 at Utrecht University. Her dissertation was titled “The role of hypoxia and metabolism in the pathogenesis of systemic sclerosis”. Supervisor was prof. Timothy Radstake; co-supervisor was dr. Wioleta Marut (both Center for Translational Immunology, UMC Utrecht).