New insights in the regulation of inflammation and fibrosis in systemic sclerosis

Several proteins of interest have been identified and characterized that are thought to play a role in the immune and fibrotic processes that occur in patients with systemic sclerosis. These proteins are potential new therapeutic targets that may offer new opportunities for the treatment of patients with SSc, says Tiago Carvalheiro who defended his PhD thesis in Utrecht on February 22.

Systemic sclerosis (SSc), also called scleroderma (sclero=hard, dermis=skin), is a rare immune-mediated fibrotic disease, characterized by hard, thickened skin areas, and often also affecting internal organs and blood vessels. In patients with SSc, a continuous inflammatory response in the connective tissue causes excessive scarring, resulting in tissue damage and eventual organ failure. The origin of SSc is largely unknown and the course of disease is unpredictable and different in each patient. In the Netherlands, there are approximately 3.000 people with SSc, with 100 new diagnoses each year. The aim of the PhD research by Tiago Carvalheiro (Center for Translational Immunology, UMC Utrecht) was to identify new proteins that play a role in SSc.

Key findings

• Downregulation of Runt-related transcription factor 3 (RUNX3) in plasmacytoid dendritic cells of patients with SSc enhances maturation of these cells and exacerbate disease in the bleomycin mouse model for SSc;
• Angiopoietin-2 is elevated in circulation of patients with SSc and promotes inflammatory activation in monocytes of patients with SSc;
• Absence of CXCL4 in mice diminishes fibrosis in the bleomycin model for SSc, while CXCL4 blocking ameliorates skin fibrosis. CXCL4 promotes myofibroblast transformation and collagen production through endothelial-to-mesenchymal transition involving metabolic changes;
• Semaphorin 4A (Sema4A) is increased in patients with SSc and induces inflammation and fibrosis in these patients;
• SPARC induces a pro-fibrotic phenotype in dermal fibroblast from patients with SSc, which is mediated by the activation of the TGF-β signaling;
• The immune inhibitory receptor LAIR-1 is broadly expressed on different monocyte subsets and macrophages in circulation and skin. Under inflammatory conditions LAIR-1 is upregulated, but upon ligation its intrinsic inhibitory capacity is functional;
• Immune cells from SSc patients do not have an intrinsic defect in LAIR-1 expression or function, however the disorganized collagen products produced under inflammatory and fibrotic conditions are dysfunctional LAIR-1 ligands, impairing its function. Moreover, LAIR-1-deficient mice show increased skin fibrosis in the bleomycin mouse model for SSc.

New therapeutic targets

In his research, several proteins of interest have been identified and characterized in both cells of the immune system and in cells responsible for the production of scar tissue. These proteins are potential new therapeutic targets that may offer new opportunities for the treatment of patients with SSc. Lastly, the underlying mechanisms of SSc are heterogeneous and can differ from patient to patient, which underlines the need to further explore these mechanisms and indicating that the therapeutic approach should be tailored to the specific characteristics of each patient.
Tiago Carvalheiro concludes: “The work in my thesis reveals several crucial processes that are dysregulated in scleroderma and contribute to inflammation and fibrosis. Because processes are rather similar in different fibrotic diseases, it is likely that this can be translated to other fibrotic conditions as well. Our findings show that there are several mechanisms that may be disrupted in scleroderma and highlight the need for better biological characterization of patients to allow for individualized treatment. Despite the limitations of mouse models and in vitro studies, our research has led to the identification of a number of potential targets for future therapies for the treatment of scleroderma.”