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Severe Asthma Research - August 2016

Christina E Ciaccio, MD, MSc

Christina E Ciaccio, MD, MSc
Allergist/Immunologist
Assistant Professor of Pediatrics
University of Chicago Medicine
Comer Children’s Hospital
Chicago, Illinois, United States

Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile

The majority of asthma exacerbations have been shown to be caused by viral infections. In adults, more than half of viral associated asthma exacerbations are due to rhinovirus. This may be due to an attenuated IFN response shown to occur in asthmatics. This manuscript examines the hypothesis that reduced TLR7 signaling is the cause of blunted IFN response in severe asthmatics. This study recruited 44 healthy subjects and 43 patients with asthma (35 with severe asthma). Overall, those with severe asthma were older, had a higher BMI, and were more likely to be atopic than healthy subjects.  Alveolar macrophages were retrieved by bronchoscopy. IFN mRNA expression was measured 24 hours after stimulation with RV16. Alveolar macrophages (AM) from patients with severe asthma (SA-AM) produced less IFNβ and IFNα mRNA and protein compared to AM from healthy controls, even after controlling for the difference in age and BMI.  No difference in TLR7 expression was seen between atopic and nonatopic subjects with severe asthma.  No difference in mRNA expression was found in any other pattern recognition receptor analyzed, including TLR8, TLR3, RIG-1 or MDA5).  Next, AMs were treated with the TLR7 agonist, imiquimod and IFN levels checked.  Even after treatment with imiquimod, production of IFN mRNA was reduced in SA-AMs compared to healthy controls.  IFN responses to Poly:IC, a TLR3, RIG-1, and MDA5 agonist, were similar in both groups.  TLR7 mRNA expression in SA-AMs was inversely correlated with the frequency of asthma exacerbation and asthma control questionnaire (ACQ) scores.  From these observations, the authors concluded that TLR7 deficiency leads to impaired IFN response to rhinovirus and recurrent lower respiratory tract infections in severe asthmatics.  Further analysis revealed that 3 miRNAs (miR-150, miR-152, miR-375) were upregulated in those with asthma and potentially targeted TLR7.  By luciferase assay, the investigators found that when all three of these miRNAs were overexpressed together, they led to a cooperative reduction in TLR7 expression and blocking of these miRNAs led to increased TLR7 expression and augmented IFN response.  In summary, this data provide evidence that miRNA mediated reduction in TLR7 expression is responsible for reduced IFN expression after rhinovirus infection in SA-AM.  Successful translation of these exciting findings may lead to a novel therapy for severe asthmatics.

Rupani H, Martinez-Nunez RT, Dennison P, Lau LC, Jayasekera M et al. Toll-like Receptor 7 Is Reduced in Severe Asthma and Linked to an Altered MicroRNA Profile. American Journal of Respiratory and Critical Care Medicine 2016; 194(1): 26-37. (doi:10.1164/rccm.201502-0280OC).

Abstract