Integrative Omics Analysis Unravels Microvascular Inflammation-Related Pathways in Kidney Allograft Biopsies
Claire Tinel, Baptiste Lamarthée, Jasper Callemeyn, Elisabet Van Loon, Virginia Sauvaget, Lise Morin, Laïla Aouni, Marion Rabant, Wilfried Gwinner, Pierre Marquet, Maarten Naesens, Dany Anglicheau
Abstract
In solid-organ transplantation, microRNAs (miRNAs) have emerged as key players in the regulation of allograft cells function in response to injury. To gain insight into the role of miRNAs in antibody-mediated rejection, a rejection phenotype histologically defined by microvascular inflammation, kidney allograft biopsies were subjected to miRNA but also messenger RNA (mRNA) profiling. Using a unique multistep selection process specific to the BIOMARGIN study (discovery cohort, N=86; selection cohort, N=99; validation cohort, N=298), six differentially expressed miRNAs were consistently identified: miR-139-5p (down) and miR-142-3p/150-5p/155-5p/222-3p/223-3p (up). Their expression level gradually correlated with microvascular inflammation intensity. The cell specificity of miRNAs target genes was investigated by integrating their in vivo mRNA targets with single-cell RNA sequencing from an independent allograft biopsy cohort. Endothelial-derived miR-139-5p expression correlated negatively with MHC-related genes expression. Conversely, epithelial-derived miR-222-3p overexpression was strongly associated with degraded renal electrolyte homeostasis and repressed immune-related pathways. In immune cells, miR-150-5p regulated NF-κB activation in T lymphocytes whereas miR-155-5p regulated mRNA splicing in antigen-presenting cells. Altogether, integrated omics enabled us to unravel new pathways involved in microvascular inflammation and suggests that metabolism modifications in tubular epithelial cells occur as a consequence of antibody-mediated rejection, beyond the nearby endothelial compartment.