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  • Greer Arthur

Do we need to silence microRNAs in severe asthma?

Pull apart and decode the human genome and you’ll find, rather surprisingly perhaps, that only 2% of it contains protein-coding genes. The majority of the leftover genes are transcribed into appropriately named non-protein-coding RNA (ncRNA). But, rather than simply existing purposelessly, these ncRNA molecules perform many crucial roles, such as the regulation of gene expression, for instance, which is controlled by a particular group of ncRNAs known as microRNAs (shortened to miRNAs). By binding to mRNA molecules and labelling them for degradation, miRNAs can suppress gene expression, and hence prevent the production of particular proteins.

In humans, over one thousand miRNAs have been discovered, but a complete archive of their many targets and functions has yet to be created. With an ability to downregulate or abolish protein expression and potentially cause cellular or tissue malfunction, it is likely that at least some miRNAs contribute to disease processes. In a study published in the American Journal of Respiratory and Critical Care Medicine in January this year, Hitasha Rupani, Tilman Sanchez-Elsner and colleagues from the University of Southampton have found that miRNAs play a role in severe asthma by suppressing the expression of a key pattern-recognition receptor of the immune system, toll-like receptor 7 (TLR7).

In severe asthma, a principle failing of the airways is their inability to retaliate appropriately to viral infections; patients with asthma suffer from a higher frequency of viral infections, which often provoke exacerbations. Healthy airways, in contrast, proficiently identify pathogens and initiate suitable immune responses to eliminate the infection. Among the many mechanisms employed by healthy airways to maintain this level of protection, toll-like receptors (TLRs), a type of pattern-recognition receptor, are expressed and recognise specific types of viruses, and then alert the innate immune system to their presence.

One particular receptor, TLR7, whose impaired function in asthmatic immune cells made it a principle focus of this study, specialises in identifying single-stranded RNA viruses such as rhinovirus, which is responsible for more than 60% of viral-induced exacerbations in adults with asthma.

In typical situations, when TLR7 is activated by rhinovirus it initiates the production of a cytokine known as interferon (IFN), which was described more than 50 years ago as “anti-viral” because it inhibits the replication of influenza virus.[1] Since this original discovery we now know that IFNs, which have now been grouped into three types (IFN-I to -III), prevent viral replication by interfering with viral RNA and protein transcription and translation, respectively.[2]

Somewhat unsurprisingly, links between an IFN deficiency and a vulnerability to rhinovirus infection and asthma exacerbations have been made. This IFN deficiency is thought to be caused, at least in part, by alveolar macrophages, phagocytic immune cells which feature prominently in the response to rhinovirus infection. In severe asthma, alveolar macrophages produce less IFN, and this may be due to altered TLR7 expression by the macrophages.[3,4] In support of this theory, Rupani and Sanchez-Elsner found that the number of exacerbations and disease control in severe asthma were inversely associated with the level of TLR7 expression in alveolar macrophages: the less TLR7 expressed by the macrophages, the more exacerbations and poorer asthma control patients seemed to have.

An important feature of alveolar macrophages in severe asthma is their inability to perform effective phagocytosis.[5,6] While this has important implications in other types of infection, this is not how macrophages tackle single-stranded viruses such as rhinovirus. Instead, macrophages engulf rhinovirus particles via receptor-mediated endocytosis,[7] which triggers IFN production by the macrophages. Since TLR7 activation normally leads to IFN production, Rupani and Sanchez-Elsner asked whether defective TLR7 may account for IFN deficiency and a susceptibility to viral infections in severe asthma. If so, recovering TLR7 expression and function could be a starting point for new asthma treatments.

By quantifying TLR7 mRNA and protein in isolated alveolar macrophages, Rupani and Sanchez-Elsner found that macrophages from patients with severe asthma expressed significantly less TLR7 than macrophages taken from healthy individuals. This lack of TLR7 was noticeably explicit, since other pattern-recognition receptors and proteins involved in preventing viral replication such as MyD88 and TLR3 were normal. Also of note, a similar difference in TLR7 expression was not seen between mild asthma and health, so Rupani and Sanchez-Elsner proposed that TLR7 deficiency could be related to asthma severity.

Severe asthmatic alveolar macrophages also produced far less IFN mRNA and protein than healthy macrophages when stimulated with either rhinovirus or a specific synthetic TLR7 agonist, imiquimod. As well as confirming a clear difference between alveolar macrophages in severe asthma, this also demonstrated that low TLR7 expression was responsible for poor IFN production. By treating the macrophages with a variety of viruses, the researchers found that the effect of low TLR7 appeared to be a dilemma unique to infection with single-stranded RNA viruses, since severe asthmatic alveolar macrophages had no problem producing IFN when attacking double-stranded viruses.

To identify the cause of differential TLR7 expression in alveolar macrophages in health and disease, Rupani and Sanchez-Elsner assessed whether TLR7 expression was being suppressed by miRNAs in severe asthma. By comparing the expression of miRNAs in alveolar macrophages from patients with severe asthma and healthy individuals, they found that three specific miRNAs (miR-150, miR-152 and miR-375) were elevated in macrophages from severe asthmatics. Interestingly, experiments showed that administration of steroids to the macrophages did not cause an increase in miRNAs, so steroid treatment in severe asthmatic patients was unlikely to be responsible for miRNA expression and TLR7 suppression. Instead, the elevation of these miRNAs could be an inherent and imperative difference between diseased and healthy macrophages. However, precisely why these miRNAs are elevated has yet to be discovered.

Using a luciferase reporter assay, the researchers found that each miRNA targeted TLR7 expression by binding to their complementary sequences within the 3’ untranslated region of the gene. The miRNAs could also bind simultaneously to suppress TLR7 expression even further. As a result, blocking these miRNAs in alveolar macrophages restored TLR7 expression, which subsequently allowed the macrophages to release substantially more IFN in the presence of rhinovirus.

By exploring the ability of miRNAs to suppress specific genes, this study has demonstrated that miRNAs could play a significant role in severe asthma by inhibiting TLR7 expression in alveolar macrophages, and thereby prevent the airways from mounting an effective anti-viral response against rhinovirus. As stipulated by current guidelines, prevention of disease exacerbations remains a major goal of asthma treatment. Consequently, if this suppression of TLR7 could be prohibited, using miRNA-specific blockers such as antagomirs, for instance, the impaired anti-viral response in severe asthma could be corrected and exacerbations avoided.

Image source: Enzymlogic


  1. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proceedings of the Royal Society of London B: Biological Sciences 1957; 147(927):258-67

  2. Sadler AJ, Williams BRG. Interferon-inducible antiviral effectors. Nature Reviews Immunology 2008; 8(7): 559-568

  3. Contoli M, Message SD, Laza-Stanca V, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nature Medicine 2006; 12: 1023-1026

  4. Sykes A, Edwards MR, Macintyre J, et al. Rhinovirus 16-induced IFN-alpha and IFN-beta are deficient in bronchoalveolar lavage cells in asthmatic patients. Journal of Allergy and Clinical Immunology 2012; 129: 1506-1514 e1506

  5. Simpson JL, Gibson PG, Yang IA, et al. Impaired macrophage phagocytosis in non-eosinophilic asthma. Clinical and Experimental Allergy 2013; 43(1): 29-35

  6. Liang Z, Zhang Q, Thomas CM, et al. Impaired macrophage phagocytosis of bacteria in severe asthma. Respiratory Research 2014; 15: 72

  7. Papi A, Johnson SL. Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappaB-mediated transcription. The Journal of Biological Chemistry 1999; 274: 9707-9720

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