Review Article
MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases

https://doi.org/10.1016/j.trsl.2011.01.007Get rights and content

MicroRNAs (miRNAs) are newly discovered, small, noncoding ribonucleic acids (RNAs) that play critical roles in the regulation of host genome expression at the posttranscriptional level. During last 20 years, miRNAs have emerged as key regulators of various biological processes including immune cell lineage commitment, differentiation, maturation, and maintenance of immune homeostasis and normal function. Thus, it is not surprising that dysregulated miRNA expression patterns now have been documented in a broad range of diseases including cancer as well as inflammatory and autoimmune diseases. This rapidly emerging field has revolutionized our understanding of normal immunoregulation and breakdown of self-tolerance. This review focuses on the current understanding of miRNA biogenesis, the role of miRNAs in the regulation of innate and adaptive immunity, and the association of miRNAs with autoimmune diseases. We have discussed miRNA dysregulation and the potential role of miRNAs in systemic lupus erythematosus (SLE), rheumatoid arthritis, and multiple sclerosis. Given that most autoimmune diseases are female-predominant, we also have discussed sex hormone regulation of miRNAs in inflammatory responses, with an emphasis on estrogen, which now has been shown to regulate miRNAs in the immune system. The field of miRNA regulation of mammalian genes has tremendous potential. The identification of specific miRNA expression patterns in autoimmune diseases as well as a comprehensive understanding of the role of miRNA in disease pathogenesis offers promise of not only novel molecular diagnostic markers but also new gene therapy strategies for treating SLE and other inflammatory autoimmune diseases.

Section snippets

miRNA Biogenesis and Action

Most mammalian miRNA genes (about 80%) have been identified in the intron region of either protein coding or nonprotein coding transcripts. Only a few miRNA genes (20%) are located in the exon region of noncoding RNAs.24, 25 Some miRNA genes could be either exonic or intronic miRNAs depending on the alternative splicing pattern of host genes.24, 26 The miRNA biogenesis pathways and their regulation have been studied extensively in last 10 years and have been well reviewed in recent publications.

The Role of miRNA in Immune System Development and Normal Function

During the last several years, mounting evidence has emerged to show that miRNAs are critical not only for the development of the immune system but also for the function of both innate and adaptive arms of the immune system.18, 40, 41, 42, 43, 44, 45 In the following sections, we will discuss the current relevant findings with regard to the roles of miRNAs in the regulation of innate immunity, adaptive immunity, autoimmunity, and inflammation.

miRNAs in the Development and Prevention of Autoimmunity

To maintain tolerance, many checkpoints are present at both central and peripheral lymphoid organ levels. These checkpoints ensure that autoreactive T and B cells that are routinely and randomly generated during lymphogenesis are either deleted or silenced.84, 85 However, in some circumstances, the self-reactive lymphocytes escape the checkpoints and survive in peripheral lymphoid tissues. Once activated, these autoreactive cells mount a devastating attack on self-tissues, leading to the

Estrogen, miRNA, and Autoimmune Diseases

A striking common feature of many autoimmune diseases in both humans and experimental animal models is that females are more susceptible to autoimmune conditions than males.128, 129, 130 More than 85% of patients with thyroiditis, scleroderma, lupus, and Sjögren’s syndrome are women.131 The female-to-male ratios for SLE, RA, and MS are 9–13:1, 2–4:1, and 2:1, respectively.128, 130 In addition to genetic factors such as X-chromosome abnormalities, sex hormones such as estrogens and androgens are

Other Potential Causes of miRNA Dysfunction in SLE

In addition to the hormonal factors discussed, genetic and environmental factors, 2 key factors that are involved in autoimmune disease etiology, also may contribute to lupus pathogenesis by altering the expression and/or function of miRNAs (Fig 4).115, 172 It has been shown that the genetic polymorphism in miRNA genes and the 3′UTR sequences of its target genes, and translocation, gene amplification or deletion in host genome all contribute to dysregulated miRNA expression and/or function in

Conclusion and Future Direction

Although miRNAs were recognized as key regulators of mammalian genome only a few short years ago, a stunning pace of publications has occurred documenting the physiological and pathological roles of miRNA in the immune system. A single miRNA may exert diverse immunoregulatory function, which may be specific to developmental stages and the microenvironment of different types of immune cells. miR-146a and miR-155 are 2 well studied miRNAs, which have been shown to play a critical role in the

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    Supported by a Lupus Foundation of America Novel Pilot Project (208-11-110B-033-918-1) grant, a Virginia-Maryland Regional College of Veterinary Medicine Intramural Research Competition Grant (IRC 17385), and in part by the National Institutes of Health (RO1AI051880).

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