MicroRNA regulation of lymphocyte tolerance and autoimmunity
Laura J. Simpson, K. Mark Ansel
Laura J. Simpson, K. Mark Ansel
Published June 1, 2015
Citation Information: J Clin Invest. 2015;125(6):2242-2249. https://doi.org/10.1172/JCI78090.
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Review Series

MicroRNA regulation of lymphocyte tolerance and autoimmunity

Abstract

Understanding the cell-intrinsic cues that permit self-reactivity in lymphocytes, and therefore autoimmunity, requires an understanding of the transcriptional and posttranscriptional regulation of gene expression in these cells. In this Review, we address seminal and recent research on microRNA (miRNA) regulation of central and peripheral tolerance. Human and mouse studies demonstrate that the PI3K pathway is a critical point of miRNA regulation of immune cell development and function that affects the development of autoimmunity. We also discuss how miRNA expression profiling in human autoimmune diseases has inspired mechanistic studies of miRNA function in the pathogenesis of multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and asthma.

Authors

Laura J. Simpson, K. Mark Ansel

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Figure 2

miRNA regulation of the PI3K pathway.

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miRNA regulation of the PI3K pathway. PI3K inhibitors are currently in c...
PI3K inhibitors are currently in clinical trials for acute and advanced leukemia (ClinicalTrials.gov identifiers NCT01756118 and NCT01396499), B and T cell lymphoma (NCT02049541, NCT02017613, NCT01693614, NCT01282424, NCT01796470, NCT02367040, NCT01306643, NCT01719250, NCT01088048, NCT02258555, NCT01300026, and NCT01705847), asthma (NCT01653756), and allergic rhinitis (NCT01066611 and NCT00836914), and preclinical data support their therapeutic potential in autoimmune diseases, as well (95). The immune system is highly sensitive to manipulation of PI3K signaling, and this pathway is subject to several layers of regulation that permit fine-tuning of signal output. Just a two-fold change in PI3K signal activity through Akt is sufficient to alter lymphocyte homeostasis and induce autoimmunity in mice (34). This degree of fine-tuning falls well within the range of regulation mediated by miRNAs. The PI3K pathway is strictly regulated by the phosphatases PTEN and SHIP, which dephosphorylate PI3K products and/or limit substrate availability. PTEN is a prominent target of many miRNAs (miR-17~92 and miR-181 family members) in many different immune cell types (Th1, Th2, Th17, Tfh, CD8 T cells, and B cells). SHIP is a prominent target of miR-155 and appears to play an important role in its proinflammatory functions in several cell lineages. miRNAs also modulate PI3K signaling by targeting downstream signaling mediators and inhibitors. Understanding which miRNAs are expressed in specific cell types, as well as understanding the varying limiting roles played by their targets, will lead to a more comprehensive understanding of miRNA regulation of cell fates and behaviors.