IL-6 signalling contributes to the pathogenesis of uraemic calciphylaxis

Uraemic calciphylaxis is a rare disease characterized by subcutaneous vessel thrombosis and ulcerative skin necrosis that predominantly affects patients with kidney failure. The disease results in substantial morbidity and mortality, but the pathogenesis is unclear and no curative therapies are available. Now, a new study reports a pathogenic role of IL-6–tissue factor (TF) signalling in uraemic calciphylaxis.

The researchers hypothesised that a combination of systemic factors and local skin microenvironment changes trigger thrombosis and ischaemic necrosis. They found that sera from patients with uraemic calciphylaxis stimulated IL-6 signalling in human dermal microvascular endothelial cells. Furthermore, spatial transcriptomics analysis of skin biopsy samples from patients with uraemic calciphylaxis showed upregulation of genes with roles in IL-6 signalling (IL6, STAT3 and JAK1) and thrombosis (FN1) in vessels, and genes with roles in thrombosis (FN1, PLAU) and calcium homeostasis (SPP1, RUNX), as well as VEGFA, in adipose tissue. TYMP, which encodes thymidine phosphorylase, was upregulated in vessels, glands and adipose tissue. In addition, IL-6 ligand–receptor interactions between vessels, adipose tissue and glands were increased in skin samples from patients with uraemic calciphylaxis compared with skin samples from patients with kidney failure who did not have calciphylaxis. The major senders and recipients of IL-6 signalling were the microvessels.