Toll-like receptor 7 function is reduced in adolescents with asthma

Abstract

Anti-viral innate immune responses may be impaired in asthma, although the mechanisms are not well understood. Toll-like receptors (TLRs) 7 and 3 are particularly relevant for initiating responses to common respiratory viruses, as they recognise single-stranded viral RNA and double-stranded viral RNA, respectively. The aim of the present study was to investigate TLR7 and TLR3 function in 14-yr-old adolescents with asthma.Blood mononuclear cells obtained from 17 atopic asthmatics, 29 atopic, non-asthmatics and 21 healthy, non-atopic individuals, were stimulated with the TLR7 agonist imiquimod and the TLR3 agonist poly I:C. Expression of anti-viral molecules was measured by real-time PCR. Concentrations of interferon-c-inducible cytokine protein (IP)-10 and interleukin (IL)-6 were measured by ELISA.TLR7-induced myxovirus resistance protein A and 2959 oligoadenylate synthetase mRNA expression and protein levels of IP-10 were significantly lower in asthma subjects compared with healthy subjects (p50.041, p50.003 and p50.001 respectively). There was a significant negative correlation between total serum immunoglobulin E and IP-10 following TLR7 stimulation. However, TLR3-induced responses did not vary with asthma or atopy. IL-10 mRNA and IL-6 protein synthesis were similar in asthmatic and control subjects. In conclusion, TLR7 function is reduced in adolescents with asthma and this may contribute to susceptibility to respiratory viral infections.KEYWORDS: Asthma, innate immunity, Toll-like receptor, virus V iral respiratory infections, especially with rhinovirus (RV), are a major cause of asthma exacerbations in children and adults [1][2][3]. Adults with asthma do not necessarily have more frequent RV infections than healthy individuals, but when RV infections occur they induce more frequent and longer lasting lower respiratory tract symptoms [4].The mechanisms by which viral infections aggravate airway inflammation and hyperresponsiveness in asthma are complex and not fully understood, although defects in anti-viral immune responses are increasingly recognised. Viraemia during acute RV infection is more commonly detected in children with acute asthma exacerbations than in non-asthmatic children with colds [5], suggesting that asthma is associated with a reduced ability to limit systemic spread of virus. Moreover, RV RNA can be detected in respiratory secretions in .40% of asthmatic children several weeks after an acute exacerbation [6], implying a reduced capacity to either clear RV from the respiratory tract, or to prevent new infections during convalescence.Recent studies have provided important insights into anti-viral innate immunity in asthma. When cultured bronchial epithelial cells are infected with RV, cells from asthmatic subjects produce less interferon (IFN)-b and IFN-l relative to healthy donors [7,8]. Alveolar macrophages and circulating leukocytes from asthmatics also appear to have a deficient capacity to synthesise type I and type III IFN [7,9,10], suggesting that the impaired anti-viral re...

Innate IFNs and Plasmacytoid Dendritic Cells Constrain Th2 Cytokine Responses to Rhinovirus: A Regulatory Mechanism with Relevance to Asthma

“…Cell separation and culture PBMC were isolated from heparinized blood by density gradient centrifugation, as previously described (13), and cultured at 1 3 10 6 PBMC in 24 culture plates together with RV16 at a multiplicity of infection of 5. Control cultures contained medium alone.…”

“…RV-stimulated alveolar macrophages from asthmatics produce less IFN-l than alveolar macrophages from healthy individuals (7). PBMC from asthmatic children and adults secrete less IFN-a following in vitro exposure to viruses (11,12), and this is associated with reduced function of TLR7, the receptor for viral ssRNA (13). Plasmacytoid dendritic cells (pDC) are a potent source of type-I IFN synthesis during virus infections (14), and numerical changes in circulating pDC have been linked both to asthma development in young children (15) and to established asthma in adults (16).…”

Toll-like Receptor 7 Rapidly Relaxes Human Airways

“…A role for TLR7 in the development of virus-induced airway hyperreactivity has been proposed, because TLR7 activation causes a proinflammatory type 1 T-helper cell (Th1) immune response (8) and because TLR7 polymorphisms have been associated with asthma (9). In patients with asthma, however, TLR7 responses were reduced (10). Furthermore, in mouse models of allergic airway inflammation, the TLR7 imidazoquinoline agonists imiquimod (R837) and resiquimod (R848) reduced airway hyperreactivity, airway eosinophilia, goblet cell hyperplasia, and smooth muscle hypertrophy (11)(12)(13)(14), whereas TLR7 knockout mice were prone to the development of asthma-like airway pathology after pneumovirus infection (15).…”

Role of Toll-like receptors in the development of allergic inflammation in asthma

“…TLR7 is expressed in natural killer T cells (NKT) which are capable of secretion of interferon γ that supports the development of Th1 response [17]. Moreover, it has been shown that adolescents with asthma have reduced TLR7 function that possibly increases their susceptibility to viruses causing respiratory diseases [18].…”