MINERVA · Micro-RNAs of neutrophils in renal ANCA-associated vasculitis

Micro-RNAs of neutrophils in renal ANCA-associated vasculitis

Activation of neutrophils by ANCA (“Anti-Neutrophil Cytoplasm Antibodies”) and subsequent microvascular endothelial cell damage is the main feature of ANCA-associated vasculitis (AAV), a severe autoimmune disease that often targets the kidney. There is no specific treatment for AAV to date and 25% of patients with renal damage evolve towards end-stage renal disease, requiring dialysis and kidney transplantation. In addition, there is no reliable biological marker of the disease activity available, which makes the diagnostic, follow-up and treatment of patients difficult. Therefore, the identification of new therapeutic targets and non-invasive biomarkers constitutes a major clinical challenge to improve AAV patients care and to ameliorate their renal outcome. Micro-RNAs (miRNA) are well established as critical regulators of major biological responses in various cell types, and have been shown to be involved in the pathophysiology of many diseases, including autoimmune diseases. In addition, miRNAs are actively secreted by cells within extracellular vesicles (EV) and are thus detected in the circulation and other biological fluids. Therefore, secreted miRNAs have been proposed as promising non-invasive biomarkers for a variety of human pathologies. Besides, accumulating data indicate that secreted miRNAs actively participate to intercellular cross-talks in various physiological and pathological situations. Indeed, miRNAs released by a cell within EVs can be transferred to another “recipient” cell, where they function to regulate target genes and subsequent biological responses. Recent studies have shown that neutrophils activated by ANCA release EVs that can induce EC activation and damage. This strongly suggests a pathogenic role for neutrophil-derived EVs in the development of vascular endothelial lesions during AAV. However, the mechanisms by which these EVs can induce EC damage and the pathophysiological role of miRNAs they may contain are still completely unknown. More generally, there is still very little data available about the expression and function of miRNAs in association with AAV. The overall objective of the MINERVA project was to identify miRNAs deregulated in ANCA-activated neutrophils and released in the circulation within EVs, which participate in the development of EC activation and damage over the course of AAV. The first objective was to identify miRNAs that are differentially expressed in ANCA-activated neutrophils and in EVs they release over the course of AAV. The second objective was to determine if neutrophils exposed to ANCA communicate with EC through the secretion of miRNA-containing EVs. The third objective was to analyse the function of identified miRNAs in the regulation of EC responses (activation, lesion/repair). While miRNAs are emerging as new therapeutic tools and biomarkers for several diseases, this translational study provides the first data regarding the expression and function of neutrophil miRNAs in AAV and may therefore pave the way for novel promising miRNA-targeted therapeutic options in these patients.

Data: CORDIS, © European Union