Profile of circulating extracellular vesicles microRNA correlates with the disease activity in granulomatosis with polyangiitis

Abstract

Granulomatosis with polyangiitis is a chronic systemic inflammation of small vessels characterized by circulating anti-proteinase 3 antibodies. MicroRNA are short transcripts specifically inhibiting protein translation. Neutrophils can release extracellular vesicles. In this study we characterised profile of microRNA trafficked by extracellular vesicles in GPA. Fifty patients with GPA were enrolled in the study, 25 at acute phase and 25 in remission. Extracellular vesicles were isolated from the blood serum, characterized by their number, size distribution. Following unbiased screening for microRNA expression, differentially expressed candidates were measured by quantitative real-time PCR. Circulating DNA-myeloperoxidase complexes and apoptosis-related transcripts in peripheral blood neutrophils were quantified. We identified four differentially expressed microRNAs from extracellular vesicles in granulomatosis with polyangiitis. MirRs-223-3p, 664a-3p, 200b-3p were overexpressed and miR-769-5p suppressed in the disease. A distinction between GPA and healthy controls was the best for miR-223-3p, whereas miR-664a-3p discriminated between active vs. remission of GPA. Correct classification of the disease based on multivariate discriminant analysis was between 92% for acute phase and 85% for all study participants. Bioinformatics tools identified genes transcripts potentially targeted by the microRNAs belonging to pathways of focal adhesion, mTOR signaling and neutrophil extracellular traps formation. Two microRNAs positively corelating with the disease activity were involved in neutrophil extracellular traps formation and apoptosis inhibition. A comprehensive characteristics of microRNAs trafficked in bloodstream inside extracellular vesicles correlates well with our understanding of the mechanisms of granulomatosis with polyangiitis and suggests importance of extracellular vesicles in progression of the disease.

Diagnostic plasma small extracellular vesicles miRNA signatures for pancreatic cancer using machine learning methods

“…Marcin et al. reported that miR-664a-3p was overexpressed in GPA and could discriminate between active disease and remission [20] . MiR-644a was decreased in blood and tissue samples from Lichen sclerosis (LS) patients compared with that in samples from healthy female volunteers [46] .…”

“…Multiple reports have shown that miR-664a-3p, which is genomically located in the intron of RAB3 GTPase Activating Non-Catalytic Protein Subunit 2 (RAB3GAP2), is abnormally expressed in a number of cancers, including gastric cancer, cervical cancer, osteosarcoma, breast cancer, and T-cell acute lymphoblastic leukaemia [15] , [16] , [17] , [18] , [19] . Another study demonstrated that there were increased levels of miR-664a-3p in EVs in granulomatosis with polyangiitis (GPA), which could be used to discriminate between active GPA and remission [20] . However, it is unclear whether miR-664a-3p expression is altered in pancreatic cancer tissues or plasma sEV.…”

Role of microRNAs in Immune Regulation with Translational and Clinical Applications

“…High levels of miR-30a-5p, miR-99a-5p, miR-106b-5p and miR-182-5p in urinary EVs were identified as novel biomarkers of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis [153]. Expression of miR-223-3p in circulating EVs discriminates between granulomatosis with polyangiitis (GPA) patients and healthy controls, whereas miR-664-3p was identified as a novel biomarker for disease activity [154]. Expression levels of miR-146a-5p were particularly high in histologically positive temporal artery biopsies of giant cell arteritis (GCA) patients, while levels of miR-424-5p were associated with vision disturbances [149].…”