MicroRNAs: The Missing Link in the Biology of Graft-Versus-Host Disease?

Abstract

Graft-versus-host disease (GVHD) is still the major complication of allogeneic hematopoietic stem cell transplantation. Despite extensive studies in understanding the pathophysiology of GVHD, its pathogenesis remains unclear. Recently, important functions of microRNAs have been demonstrated in various autoimmune diseases and cancers such as psoriasis and lymphoma. This review highlights the need to investigate the role of microRNAs in GVHD and hypothesizes that microRNAs may be one of the missing links in our understanding of GVHD, with the potential for novel therapeutics.

Keywords: allogeneic hematopoietic stem cell transplantation; bioinformatics; biomarkers; graft-versus-host disease; microRNAs.

Figure 1

The driving gears of GVHD. MiRNAs regulate gene expressions, chemokine and cytokine secretions while their expression is simultaneously affected by SNPs in mRNA (gene) targets. Thus, understanding the involvement of miRNAs in regulating gene expression, which ultimately affect the function of cells, will aid in our better understanding of the regulatory mechanisms involved in GVHD pathogenesis.

Figure 2

Regulation of miRNAs. Expression of miRNAs can be altered at various stages of its biogenesis by genomic (SNPs and mutations) and epigenetic alterations. Changes in the expression and function of Drosha and Dicer, which are part of the miRNA processing machinery, can also lead to the deregulation of mature miRNAs [adapted from Ref. (37)].

Figure 3

Graft-versus-host disease signaling pathway and miRNA interactions obtained using IPA. Classical GVHD signaling pathway was selected from the IPA knowledge base and eight miRNAs were identified to interact with the various components of the pathway. Chemokines and genes are represented as nodes of various shapes and the biological relationship and interactions between them are represented as a line. Direct experimentally proven interactions are represented with a solid line, while indirect interactions are shown as a dashed line. All the interactions are supported by at least one reference from either the literature or from the information available in the Ingenuity Pathways Knowledge Base. The direction of the interaction is indicated with the arrow head. miR-146a-5p and miR-155-5p are mature miRNAs while miR-515, miR-346, miR-143, miR-373, miR-31, and miR-29 could be primary, precursor or even mature forms of miRNAs.

Figure 4

Therapeutic applications of miRNAs. MiRNA antagonists, which are modified oligonucleotides with complementary sequences to the endogenous miRNAs, can be used to degrade over-expressed miRNAs. Loss of function of the endogenous miRNA prevents it being processed by RISC. MiRNA mimics are also oligonucleotides, but they replace the lost function due to the disease state of the cell [adopted from Ref. (117)].