MicroRNAs: Essential players in the regulation of inflammation
2013; Elsevier BV; Volume: 132; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2013.04.011
ISSN1097-6825
Autores Tópico(s)Extracellular vesicles in disease
ResumoRegulation of inflammatory responses is ensured by coordinated control of gene expression in participating immune system and tissue cells. One group of gene expression regulators, the functions of which have recently been started to be uncovered in relation to any type of inflammatory condition, is a class of short single-stranded RNA molecules termed microRNAs (miRNAs). miRNAs function together with partner proteins and mainly cause gene silencing through degradation of target mRNAs or inhibition of translation. A particular miRNA can have hundreds of target genes, and thereby miRNAs together influence the expression of a large proportion of proteins. The role of miRNAs in the immune system has been extensively studied since the discovery of miRNAs in mammalian cells approximately 10 years ago. The purpose of the current review is to provide an overview on the functions of miRNAs in the regulation of inflammation, with a specific focus on the mechanisms of allergic inflammation. Because recent studies clearly demonstrate the presence of extracellular miRNAs in body fluids and propose the involvement of miRNAs in cell-cell communication, we will also highlight findings about functions of extracellular miRNAs. The possible use of miRNAs as biomarkers, as well as miRNA-related novel treatment modalities, might open a new future for the diagnosis and treatment of many inflammatory conditions, including allergic diseases. Regulation of inflammatory responses is ensured by coordinated control of gene expression in participating immune system and tissue cells. One group of gene expression regulators, the functions of which have recently been started to be uncovered in relation to any type of inflammatory condition, is a class of short single-stranded RNA molecules termed microRNAs (miRNAs). miRNAs function together with partner proteins and mainly cause gene silencing through degradation of target mRNAs or inhibition of translation. A particular miRNA can have hundreds of target genes, and thereby miRNAs together influence the expression of a large proportion of proteins. The role of miRNAs in the immune system has been extensively studied since the discovery of miRNAs in mammalian cells approximately 10 years ago. The purpose of the current review is to provide an overview on the functions of miRNAs in the regulation of inflammation, with a specific focus on the mechanisms of allergic inflammation. Because recent studies clearly demonstrate the presence of extracellular miRNAs in body fluids and propose the involvement of miRNAs in cell-cell communication, we will also highlight findings about functions of extracellular miRNAs. The possible use of miRNAs as biomarkers, as well as miRNA-related novel treatment modalities, might open a new future for the diagnosis and treatment of many inflammatory conditions, including allergic diseases. GlossaryACTIVATION-INDUCED CYTIDINE DEAMINASE (AID)AID is an enzyme that promotes affinity maturation and class-switching of immunoglobulins. AID deficiency can cause autosomal recessive hyper-IgM syndrome.APOPTOSISApoptosis is the major naturally occurring programmed cell death pathway. It is associated with chromosomal DNA fragmentation and production of cell fragments called apoptotic bodies, which phagocytic cells can quickly remove so that surrounding tissue is not influenced.CYCLIC AMP-RESPONSIVE ELEMENT-BINDING PROTEIN 1 (CREB)CREB is a transcription factor downstream of G protein–coupled receptor signals that activates transcription of CRE element–containing genes. CREB binds to CBP/p300, which is a coactivator protein functioning as a histone acetyltransferase that allows chromatin remodeling and activation of gene transcription.EPIGENETICGene expression changes that can be heritable and self-perpetuating but that do not change the genetic code (ie, DNA sequence) and therefore can alter transcription in a faster time frame. Epigenetic modifications include histone acetylation and methylation and DNA methylation.IL-17IL-17 is the defining interleukin produced by TH17 cells, which are important in the immune response to extracellular pathogens and autoimmunity. IL-17 is induced by IL-1, IL-6, and IL-23. IL-17 increases IL-1β and IL-6 levels and recruitment of neutrophils. IL-17E is also known as IL-25, is produced by TH2 cells and mast cells, and promotes eosinophilic diseases.IL-22IL-22 belongs to the IL-10 family of cytokines and is produced mainly by activated T cells. IL-22 initiates innate immune responses against bacterial pathogens, especially in epithelial cells. Similar to IL-10, IL-22 also promotes survival of epithelial cells in the skin, lung, and gut.INFLAMMASOMEInflammasomes are intracellular multiprotein complexes that respond to pathogen-associated molecular patterns and damage-associated molecular patterns, which bind to nucleotide-binding oligomerization domain–like receptors (NLRs). NLRs recruit adaptor molecules that activate caspase-1 to subsequently increase inflammatory cytokine secretion, especially IL-1β.KRUPPEL-LIKE FACTOR (KLF) 5The KLF transcription factors KLF1 to KLF17 are zinc finger domain–containing proteins. KLF4 and KLF5 are 2 closely related members of the family that are both highly expressed in epithelial tissues. KLF5 is expressed in proliferating cells and generally stimulates proliferation, including that of fibroblasts and epithelial cells. In contrast, KLF4 inhibits cell proliferation and is expressed in cells that are terminally differentiated.M2Also known as alternatively activated macrophages, M2 macrophages develop under the influence of IL-4 and IL-13. Classical M1 macrophages are generated by IFN-γ and TLR signaling. There is significant plasticity in the macrophage subtypes, which are defined by their protein profile, such as the production of arginase 1 by M2 macrophages.POLYCISTRONIC TRANSCRIPTA polycistronic transcript contains multiple coding regions that allow a single transcript to code for multiple proteins or noncoding RNAs, including miRNAs.PROMOTER, INTRON, EXON, 3′ UNTRANSLATED REGION (3′UTR)Elements that define gene structure and control gene expression. The promoter is located upstream of the gene. Transcription factors and regulators bind to the promoter and control the initiation and rate of the gene expression. The intron is a sequence within a gene that is removed by means of RNA splicing while the final mRNA product of a gene is being generated by joining the exons. The 3′UTR of mRNA is a part of the last exon, which is located downstream of the stop codon and therefore is not translated. 3′UTR can be used to regulate the translation rate and message stability.SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 1 AND STAT6STATs are a family of transcription factors that require phosphorylation and dimerization to activate gene transcription in response to Janus-activated kinase (JAK). STAT6 is activated by IL-4 and is important for the development of TH2 cells. STAT1 is activated by IFN-γ and is essential for development of TH1 cells.SMALL INTERFERING RNA (siRNA)siRNAs have become an important scientific tool to suppress gene expression by specifically targeting a gene transcript and interfering with its mRNA level. As such, siRNAs effectively function as a transient gene “knockdown” tool. In insects and plants naturally occurring siRNAs are part of antiviral mechanism and also function in epigenetic shaping of chromatin.TOLL-LIKE RECEPTOR (TLR)Essential members of the innate immune system, TLRs are pattern recognition receptors, the main function of which is to recognize different pathogens. TLR4 binds LPS from gram-negative bacteria. TLR2 recognizes cell-wall components, such as peptidoglycan and lipoprotein from gram-positive bacteria. TLR7 and TLR8 bind single-stranded RNA and are important for antiviral defense.THYMIC STROMAL LYMPHOPOIETIN (TSLP)TSLP is a cytokine expressed in activated epithelial cells. TSLP enhances the maturation of myeloid (CD11c+) dendritic cells and promotes antigen presentation and TH2 cell differentiation. TSLP plays a significant role in patients with atopic dermatitis and asthma and was associated with eosinophilic esophagitis in a genome-wide association study.The Editors wish to acknowledge Seema S. Aceves, MD, PhD, for preparing this glossary. AID is an enzyme that promotes affinity maturation and class-switching of immunoglobulins. AID deficiency can cause autosomal recessive hyper-IgM syndrome. Apoptosis is the major naturally occurring programmed cell death pathway. It is associated with chromosomal DNA fragmentation and production of cell fragments called apoptotic bodies, which phagocytic cells can quickly remove so that surrounding tissue is not influenced. CREB is a transcription factor downstream of G protein–coupled receptor signals that activates transcription of CRE element–containing genes. CREB binds to CBP/p300, which is a coactivator protein functioning as a histone acetyltransferase that allows chromatin remodeling and activation of gene transcription. Gene expression changes that can be heritable and self-perpetuating but that do not change the genetic code (ie, DNA sequence) and therefore can alter transcription in a faster time frame. Epigenetic modifications include histone acetylation and methylation and DNA methylation. IL-17 is the defining interleukin produced by TH17 cells, which are important in the immune response to extracellular pathogens and autoimmunity. IL-17 is induced by IL-1, IL-6, and IL-23. IL-17 increases IL-1β and IL-6 levels and recruitment of neutrophils. IL-17E is also known as IL-25, is produced by TH2 cells and mast cells, and promotes eosinophilic diseases. IL-22 belongs to the IL-10 family of cytokines and is produced mainly by activated T cells. IL-22 initiates innate immune responses against bacterial pathogens, especially in epithelial cells. Similar to IL-10, IL-22 also promotes survival of epithelial cells in the skin, lung, and gut. Inflammasomes are intracellular multiprotein complexes that respond to pathogen-associated molecular patterns and damage-associated molecular patterns, which bind to nucleotide-binding oligomerization domain–like receptors (NLRs). NLRs recruit adaptor molecules that activate caspase-1 to subsequently increase inflammatory cytokine secretion, especially IL-1β. The KLF transcription factors KLF1 to KLF17 are zinc finger domain–containing proteins. KLF4 and KLF5 are 2 closely related members of the family that are both highly expressed in epithelial tissues. KLF5 is expressed in proliferating cells and generally stimulates proliferation, including that of fibroblasts and epithelial cells. In contrast, KLF4 inhibits cell proliferation and is expressed in cells that are terminally differentiated. Also known as alternatively activated macrophages, M2 macrophages develop under the influence of IL-4 and IL-13. Classical M1 macrophages are generated by IFN-γ and TLR signaling. There is significant plasticity in the macrophage subtypes, which are defined by their protein profile, such as the production of arginase 1 by M2 macrophages. A polycistronic transcript contains multiple coding regions that allow a single transcript to code for multiple proteins or noncoding RNAs, including miRNAs. Elements that define gene structure and control gene expression. The promoter is located upstream of the gene. Transcription factors and regulators bind to the promoter and control the initiation and rate of the gene expression. The intron is a sequence within a gene that is removed by means of RNA splicing while the final mRNA product of a gene is being generated by joining the exons. The 3′UTR of mRNA is a part of the last exon, which is located downstream of the stop codon and therefore is not translated. 3′UTR can be used to regulate the translation rate and message stability. STATs are a family of transcription factors that require phosphorylation and dimerization to activate gene transcription in response to Janus-activated kinase (JAK). STAT6 is activated by IL-4 and is important for the development of TH2 cells. STAT1 is activated by IFN-γ and is essential for development of TH1 cells. siRNAs have become an important scientific tool to suppress gene expression by specifically targeting a gene transcript and interfering with its mRNA level. As such, siRNAs effectively function as a transient gene “knockdown” tool. In insects and plants naturally occurring siRNAs are part of antiviral mechanism and also function in epigenetic shaping of chromatin. Essential members of the innate immune system, TLRs are pattern recognition receptors, the main function of which is to recognize different pathogens. TLR4 binds LPS from gram-negative bacteria. TLR2 recognizes cell-wall components, such as peptidoglycan and lipoprotein from gram-positive bacteria. TLR7 and TLR8 bind single-stranded RNA and are important for antiviral defense. TSLP is a cytokine expressed in activated epithelial cells. TSLP enhances the maturation of myeloid (CD11c+) dendritic cells and promotes antigen presentation and TH2 cell differentiation. TSLP plays a significant role in patients with atopic dermatitis and asthma and was associated with eosinophilic esophagitis in a genome-wide association study. The Editors wish to acknowledge Seema S. Aceves, MD, PhD, for preparing this glossary. The innate and adaptive responses of immune system and tissue cells are under the control of a highly coordinated regulation of gene expression in all participating cells. Advances in basic biology combined with recent whole-genome and transcriptome studies demonstrate that control of protein expression levels is far more dynamic and complex than presumed. One group of gene expression regulators, the functions of which have just started to be uncovered, is a class of short single-stranded RNA molecules termed microRNAs (miRNAs). miRNAs are only 21 to 23 nucleotides long. They bind to the 3′ untranslated regions (3′UTRs) of their target mRNA through at least 6- to 8-nucleotide-long complementary sequences. They cause gene silencing mainly through degradation of target mRNAs or inhibition of translation.1Makeyev E.V. Maniatis T. Multilevel regulation of gene expression by microRNAs.Science. 2008; 319: 1789-1790Crossref PubMed Scopus (123) Google Scholar, 2Djuranovic S. Nahvi A. Green R. A parsimonious model for gene regulation by miRNAs.Science. 2011; 331: 550-553Crossref PubMed Scopus (218) Google Scholar Expression of miRNAs is often tissue specific and developmentally controlled, and it has been estimated that there are approximately 1000 different miRNAs in the human genome.3Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (5609) Google Scholar, 4Chiang H.R. Schoenfeld L.W. Ruby J.G. Auyeung V.C. Spies N. Baek D. et al.Mammalian microRNAs: experimental evaluation of novel and previously annotated genes.Genes Dev. 2010; 24: 992-1009Crossref PubMed Scopus (349) Google Scholar miRNAs usually belong to families, which consist of evolutionarily related members that partially share sequences and targets.5Burge S.W. Daub J. Eberhardt R. Tate J. Barquist L. Nawrocki E.P. et al.Rfam 11.0: 10 years of RNA families.Nucleic Acids Res. 2013; 41: D226-D232Crossref PubMed Scopus (207) Google Scholar It has recently been proposed that there are 239 different miRNA families in the human genome.6Meunier J. Lemoine F. Soumillon M. Liechti A. Weier M. Guschanski K. et al.Birth and expression evolution of mammalian microRNA genes.Genome Res. 2012; 23: 34-45Crossref PubMed Scopus (14) Google Scholar These families express altogether more than 2000 different mature miRNA sequences that are annotated to the microRNA database miRBase (http://www.mirbase.org/index.shtml).7Griffiths-Jones S. miRBase: the microRNA sequence database.Methods Mol Biol. 2006; 342: 129-138Crossref PubMed Google Scholar Because of very short complementarity to the target mRNA, a particular miRNA can have hundreds of target genes, and thereby miRNAs collectively have been suggested to influence the expression of approximately 30% of genes.1Makeyev E.V. Maniatis T. Multilevel regulation of gene expression by microRNAs.Science. 2008; 319: 1789-1790Crossref PubMed Scopus (123) Google Scholar The role of miRNAs in relation to the immune system has been extensively studied since the discovery of miRNAs in mammalian cells about 10 years ago.8O'Connell R.M. Rao D.S. Baltimore D. microRNA regulation of inflammatory responses.Annu Rev Immunol. 2012; 30: 295-312Crossref PubMed Scopus (170) Google Scholar, 9Boldin M.P. Baltimore D. MicroRNAs, new effectors and regulators of NF-kappaB.Immunol Rev. 2012; 246: 205-220Crossref PubMed Scopus (72) Google Scholar, 10O'Neill L.A. Sheedy F.J. McCoy C.E. MicroRNAs: the fine-tuners of Toll-like receptor signalling.Nat Rev Immunol. 2011; 11: 163-175Crossref PubMed Scopus (287) Google Scholar Thus far, more than 900 articles have been published about immune system–related functions of miRNAs. Here we provide an overview of miRNAs that function in the regulation of inflammatory pathways and therefore most likely affect many inflammatory conditions. miRNAs that have been shown to be directly involved in the development of allergic diseases are highlighted. Furthermore, we discuss the potential of miRNAs as biomarkers and targets of gene therapy. Because recent discoveries clearly demonstrate the presence of miRNAs in sera and propose the involvement of miRNAs in cell-cell communication, we also emphasize the latest findings about the functions of extracellular miRNAs. Like protein-coding mRNAs, miRNAs are first synthesized in the nucleus by RNA polymerase II as a part of longer transcripts, termed pri-miRNAs. Pri-miRNAs can be encoded by independent promoters, as polycistronic transcripts, or they might be embedded within the introns of protein-coding genes. As a next step, long pri-miRNAs are cleaved by the RNAse III–type endonuclease Drosha-DGCR8 (DiGeorge syndrome critical region gene 8, also known as Pasha) complex to small hairpin-like precursors, which are called pre-miRNAs (Fig 1). Pre-miRNA export to the cytoplasm is mediated by the Exportin-5–Ran-GTP complex. In the cytoplasm pre-miRNAs undergo a second round of processing by the enzyme Dicer and the generation of a short RNA duplex. One strand of the duplex is incorporated into RNA-induced silencing complex (RISC), which contains 1 of the 4 Argonaute (AGO) proteins (most frequently AGO2), and trinucleotide repeat–containing 6 protein (TNRC6), which is often called glycine-tryptophan 182-kDa protein (GW182).11Krol J. Loedige I. Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay.Nat Rev Genet. 2010; 11: 597-610Crossref PubMed Scopus (1206) Google Scholar, 12Winter J. Jung S. Keller S. Gregory R.I. Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation.Nat Cell Biol. 2009; 11: 228-234Crossref PubMed Scopus (824) Google Scholar The miRNAs that are loaded into the RISC complex bind through at least 6- to 8-nucleotide complementarity to their target mRNAs and thereby mediate repression of protein expression and induce mRNA degradation. The key protein in the RISC complex is GW182, the glycine-tryptophan repeats of which recruit multicomponent nuclease assigned as the CCR4-NOT complex. The CCR4-NOT complex inhibits translation and initiates deadenylation of mRNA.13Hafner M. Ascano Jr., M. Tuschl T. New insights in the mechanism of microRNA-mediated target repression.Nat Struct Mol Biol. 2011; 18: 1181-1182Crossref PubMed Scopus (8) Google Scholar Apparently, the recruitment of the CCR4-NOT complex by GW182 releases polyA-binding protein from the mRNA polyA tail, thereby disrupting mRNA circularization and facilitating translational repression and deadenylation.14Zekri L. Kuzuoglu-Ozturk D. Izaurralde E. GW182 proteins cause PABP dissociation from silenced miRNA targets in the absence of deadenylation.EMBO J. 2013; 32: 1052-1065Crossref PubMed Scopus (32) Google Scholar Using the Drosophila S2 cell–based controllable expression system, it has been shown that miRNAs first cause translational inhibition of their target mRNAs, followed by effects on deadenylation and decay.15Djuranovic S. Nahvi A. Green R. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay.Science. 2012; 336: 237-240Crossref PubMed Scopus (227) Google Scholar However, in mammalian cells it has been demonstrated that changes in mRNA levels closely reflect the effect of miRNAs on protein expression, which indicates that destabilization of target mRNAs is the predominant mechanism of action.16Guo H. Ingolia N.T. Weissman J.S. Bartel D.P. Mammalian microRNAs predominantly act to decrease target mRNA levels.Nature. 2010; 466: 835-840Crossref PubMed Scopus (1449) Google Scholar Although the AGO2 protein possesses intrinsic capability to cleave double-stranded RNA and thereby could initiate RNA degradation, its catalytic activity does not manifest when the RISC-miRNA complex binds to mRNA because there is rarely 100% complementarity between miRNA and mRNA. Cleavage activity of RISC-associated AGO is more common in plants, in which miRNAs are highly complementary to their targets, and RNA silencing is widely used to eliminate RNA viruses.17Molnar A. Melnyk C. Baulcombe D.C. Silencing signals in plants: a long journey for small RNAs.Genome Biol. 2011; 12: 215Crossref PubMed Scopus (45) Google Scholar In mammalian cells cleavage activity of AGO2 becomes apparent when artificial small interfering RNAs (siRNAs), which are fully complementary to their target mRNAs, are introduced into the cells. The function of siRNAs in cultured mammalian cells was first demonstrated by Elbashir et al18Elbashir S.M. Harborth J. Lendeckel W. Yalcin A. Weber K. Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.Nature. 2001; 411: 494-498Crossref PubMed Scopus (6492) Google Scholar in 2001 and has become a widely used method for the suppression of gene expression. In addition, there exists also a Dicer-independent pathway of miRNA biogenesis, which requires catalytic activity of AGO2.19Cifuentes D. Xue H. Taylor D.W. Patnode H. Mishima Y. Cheloufi S. et al.A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity.Science. 2010; 328: 1694-1698Crossref PubMed Scopus (346) Google Scholar, 20Cheloufi S. Dos Santos C.O. Chong M.M. Hannon G.J. A dicer-independent miRNA biogenesis pathway that requires Ago catalysis.Nature. 2010; 465: 584-589Crossref PubMed Scopus (392) Google Scholar Similar to protein-encoding mRNAs, the expression levels of miRNAs are regulated at the epigenetic level during transcription, processing, and nuclear export, as well as through controlled degradation.11Krol J. Loedige I. Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay.Nat Rev Genet. 2010; 11: 597-610Crossref PubMed Scopus (1206) Google Scholar Notably, miRNAs do not switch off the expression of their target genes but only reduce the amount of mRNA and protein. The influence of a single miRNA on the expression level of a single target mRNA can remain unnoticed by using current measurement methods. However, because miRNAs often target several mRNAs from the same pathway, as well as a single mRNA that can be targeted by multiple miRNAs, the influence of miRNAs becomes indispensable. Accordingly, loss of Dicer1 in mice leads to lethality early in embryonic development, suggesting a very general and essential role of miRNAs.21Bernstein E. Kim S.Y. Carmell M.A. Murchison E.P. Alcorn H. Li M.Z. et al.Dicer is essential for mouse development.Nat Genet. 2003; 35: 215-217Crossref PubMed Scopus (1053) Google Scholar Considering that the function of miRNAs is to coordinately fine tune the expression of genes, it is noteworthy that expansion of miRNA families seems to be associated with the complexity of the organism and the body plan innovations of vertebrates. This suggests that miRNAs have significantly contributed to evolution. Indeed, there are only 78 ancestral miRNA families conserved between vertebrates and invertebrates, whereas mice and human subjects possess 234 and 239 miRNA families, respectively.6Meunier J. Lemoine F. Soumillon M. Liechti A. Weier M. Guschanski K. et al.Birth and expression evolution of mammalian microRNA genes.Genome Res. 2012; 23: 34-45Crossref PubMed Scopus (14) Google Scholar Also, it should be noted that miRNAs mainly interact with the 3′UTR of mRNA, in which their binding is more efficient because of a lack of active translation.22Gu S. Jin L. Zhang F. Sarnow P. Kay M.A. Biological basis for restriction of microRNA targets to the 3' untranslated region in mammalian mRNAs.Nat Struct Mol Biol. 2009; 16: 144-150Crossref PubMed Scopus (161) Google Scholar However, in certain cases miRNAs target the coding region of mRNA. For example, miRNAs binding to Nanog, Oct4, and Sox2 protein–coding regions are capable of modulating embryonic stem cell differentiation.23Tay Y. Zhang J. Thomson A.M. Lim B. Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation.Nature. 2008; 455: 1124-1128Crossref PubMed Scopus (684) Google Scholar In addition, posttranscriptional regulation of mRNA stability and translation also depends on proteins that bind to the 3’UTR of mRNA. For instance, the presence of the AU-rich element–binding protein HuR in mRNA promotes dissociation of the RISC complex and relieves miRNA repression.24Kundu P. Fabian M.R. Sonenberg N. Bhattacharyya S.N. Filipowicz W. HuR protein attenuates miRNA-mediated repression by promoting miRISC dissociation from the target RNA.Nucleic Acids Res. 2012; 40: 5088-5100Crossref PubMed Scopus (43) Google Scholar It has also been reported that on cell-cycle arrest, miRNAs can upregulate translation.25Vasudevan S. Tong Y. Steitz J.A. Switching from repression to activation: microRNAs can up-regulate translation.Science. 2007; 318: 1931-1934Crossref PubMed Scopus (1238) Google Scholar Inflammation is a protective attempt of the organism to remove or neutralize harmful stimuli, such as pathogens, damaged cells, toxins, allergens, or irritants, and to initiate the tissue healing process. In healthy subjects the immune system functions extremely efficiently, detecting pathogens already at very low levels and trying to eliminate them before they reach harmful numbers. However, excessive and inappropriate responses can cause unreasonably strong inflammation and tissue damage.26Medzhitov R. Inflammation 2010: new adventures of an old flame.Cell. 2010; 140: 771-776Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar, 27Renz H. Brandtzaeg P. Hornef M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation.Nat Rev Immunol. 2012; 12: 9-23Google Scholar, 28Akdis C.A. Therapies for allergic inflammation: refining strategies to induce tolerance.Nat Med. 2012; 18: 736-749Crossref PubMed Scopus (74) Google Scholar The activation of inflammation involves inducers, sensors, mediators, and target tissues. Inducers, such as pathogens, allergens, irritants, and tissue damage, initiate the inflammatory response and are detected by sensors, such as Toll-like receptors (TLRs), which are present in specialized immune cells, such as tissue-resident macrophages, dendritic cells (DCs), and mast cells. They induce the production of mediators, including cytokines, such as IL-1β, TNF-α, and IL-6, and chemokines, such as CCL2 and CXCL8.26Medzhitov R. Inflammation 2010: new adventures of an old flame.Cell. 2010; 140: 771-776Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar The central activated signal transduction pathway downstream of the sensors are the nuclear factor κB (NF-κB) pathway26Medzhitov R. Inflammation 2010: new adventures of an old flame.Cell. 2010; 140: 771-776Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar and the Janus kinase–signal transducer and activator of transcription (STAT) pathway.29O'Shea J.J. Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.Immunity. 2012; 36: 542-550Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 30Stark G.R. Darnell Jr., J.E. The JAK-STAT pathway at twenty.Immunity. 2012; 36: 503-514Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar In response to tissue damage, the inflammasome and caspase-1 pathways are activated through nucleotide-binding oligomerization domain–like receptors.31Lamkanfi M. Emerging inflammasome effector mechanisms.Nat Rev Immunol. 2011; 11: 213-220Crossref PubMed Scopus (135) Google Scholar During chronic inflammation and secondary responses, activation of adaptive immunity and antigen-specific T-cell responses take place. Activation of any of these pathways has an influence on the development of allergic diseases, and miRNAs that modulate inflammatory pathways potentially might affect the development and intensity of allergic conditions as well. Numerous studies have shown that Dicer1-dependent miRNAs are also indispensable for the immune system. For instance, the Dicer1 gene is important for differentiation and functions of regulatory T (Treg) cells,32Liston A. 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