Review ArticleMicroRNA, a new paradigm for understanding immunoregulation, inflammation, and 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
References (184)
- et al.
The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14
Cell
(1993) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Phylogenetic shadowing and computational identification of human microRNA genes
Cell
(2005) - et al.
Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets
Cell
(2005) - et al.
A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes
Cell
(2006) MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing
Cell
(2003)- et al.
MicroRNAs as oncogenes and tumor suppressors
Dev Biol
(2007) - et al.
MicroRNAs: a new class of regulatory genes affecting metabolism
Cell Metab
(2006) - et al.
MicroRNA in autoimmunity and autoimmune diseases
J Autoimmun
(2009) - et al.
Genomics of microRNA
Trends Genet
(2006)
Origins and mechanisms of miRNAs and siRNAs
Cell
And now introducing mammalian mirtrons
Dev Cell
The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila
Cell
Mammalian mirtron genes
Mol Cell
MicroRNAs and immunity: tiny players in a big field
Immunity
MicroRNA control in the immune system: basic principles
Cell
MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation
Semin Cancer Biol
A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis
Cell
Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia
Blood
A cellular microRNA, let-7i, regulates toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection
J Biol Chem
Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation
FEBS Lett
Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage
Cell
MicroRNA-155 Regulates the generation of immunoglobulin class-switched plasma cells
Immunity
MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation
Immunity
MicroRNA-155 function in B Cells
Immunity
miR-181a is an intrinsic modulator of T cell sensitivity and selection
Cell
miR-150 controls B cell differentiation by targeting the transcription factor c-Myb
Cell
Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters
Cell
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses
Cell
MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development
Immunity
Multistep pathogenesis of autoimmune disease
Cell
The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans
Nature
Identification of novel genes coding for small expressed RNAs
Science
An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans
Science
An extensive class of small RNAs in Caenorhabditis elegans
Science
miRBase: microRNA sequences, targets and gene nomenclature
Nucleic Acids Res
Identification of hundreds of conserved and nonconserved human microRNAs
Nat Genet
Principles and effects of microRNA-mediated post-transcriptional gene regulation
Oncogene
The microRNA registry
Nucleic Acids Res
Dicer is essential for mouse development
Nat Genet
The functions of animal microRNAs
Nature
Dynamic regulation of miRNA expression in ordered stages of cellular development
Genes Dev
MicroRNAs: new regulators of immune cell development and function
Nat Immunol
MicroRNAs: a new emerging class of players for disease diagnostics and gene therapy
J Cell Mol Med
Understanding microRNAs in neurodegeneration
Nat Rev Neurosci
Identification of mammalian microRNA host genes and transcription units
Genome Res
Biogenesis of small RNAs in animals
Nat Rev Mol Cell Biol
MicroRNA biogenesis: coordinated cropping and dicing
Nat Rev Mol Cell Biol
Many roads to maturity: microRNA biogenesis pathways and their regulation
Nat Cell Biol
MicroRNA genes are transcribed by RNA polymerase II
EMBO J
Cited by (375)
The Psychoneuroimmunological Model of Moral Distress and Health in healthcare workers: Toward individual and system-level solutions
2024, Comprehensive PsychoneuroendocrinologyMultitask joint learning with graph autoencoders for predicting potential MiRNA-drug associations
2023, Artificial Intelligence in MedicinePrognostic utility of microRNA-145 and CD 133 in oral squamous cell carcinoma: A pilot study from Northern India
2023, Journal of Oral Biology and Craniofacial ResearchApproaches to autoimmune diseases using epigenetic therapy
2023, Epigenetics in Human Disease, Third EditionSex specificity in neonatal diseases
2023, Principles of Gender-Specific Medicine: Sex and Gender-Specific Biology in the Postgenomic Era
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).