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IL-17A Inhibits Airway Reactivity Induced by Respiratory Syncytial Virus Infection During Allergic Airway Inflammation

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IL-17A Inhibits Airway Reactivity Induced by Respiratory Syncytial Virus Infection During Allergic Airway Inflammation Thorax Online First, published on February 19, 2013 as 10.1136/thoraxjnl-2012-202404 Asthma Thorax: first published as 10.1136/thoraxjnl-2012-202404 on 19 February 2013. Downloaded from ORIGINAL ARTICLE IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation Dawn Catherine Newcomb,1 Madison G Boswell,1 Sara Reiss,1 Weisong Zhou,1 Kasia Goleniewska,1 Shinji Toki,1 Melissa T Harintho,2 Nicholas W Lukacs,3 Jay K Kolls,4 R Stokes Peebles Jr1 ▸ Additional material is ABSTRACT published online only. To view Background Viral infections are the most frequent Key messages please visit the journal online (http://dx.doi.org/10.1136/ cause of asthma exacerbations and are linked to thoraxjnl-2012-202404). increased airway reactivity (AR) and inflammation. Mice 1 infected with respiratory syncytial virus (RSV) during What is the key question? Department of Medicine, fl Vanderbilt University Medical ovalbumin (OVA)-induced allergic airway in ammation ▸ What is the role of IL-17A in airway Center, Nashville, Tennessee, (OVA/RSV) had increased AR compared with OVA or RSV inflammation and airway reactivity in a USA mice alone. Furthermore, interleukin 17A (IL-17A) was 2 clinically relevant model of asthma Department of Pathology, only increased in OVA/RSV mice. exacerbation in which viral infection occurs Microbiology, and Immunology, fl Vanderbilt University Medical Objective To determine whether IL-17A increases AR during ongoing allergic airway in ammation? Center, Nashville, Tennessee, and inflammation in the OVA/RSV model. USA Methods Wild-type (WT) BALB/c and IL-17A knockout What is the bottom line? 3Department of Pathology, (KO) mice underwent mock, RSV, OVA or OVA/RSV ▸ IL-17A negatively regulates airway reactivity University of Michigan, protocols. Lungs, bronchoalveolar lavage (BAL) fluid and/ and airway inflammation with respiratory Ann Arbor, Michigan, USA 4 or mediastinal lymph nodes (MLNs) were harvested after syncytial virus infection during ongoing allergic Department of Pediatrics, fl University of Pittsburgh, infection. Cytokine expression was determined by ELISA airway in ammation. ’ fl Children s Hospital of in the lungs or BAL uid. MLNs were restimulated with Why read on? Pittsburgh, Pittsburgh, either OVA (323–229) peptide or RSV M2 (127–135) Pennsylvania, USA ▸ IL-17A has been identified as a potential peptide and IL-17A protein expression was analysed. AR therapeutic target in asthma, and it is vital to Correspondence to was determined by methacholine challenge. understand the role of IL-17A in increased http://thorax.bmj.com/ Dr Dawn Catherine Newcomb, Results RSV increased IL-17A protein expression by allergic airway inflammation and airway Department of Medicine, fi OVA-speci c T cells 6 days after infection. OVA/RSV mice reactivity with viral infections during ongoing Vanderbilt University Medical had decreased interferon-β protein expression compared Center, 1161 21st, Avenue, allergic airway inflammation. T-1218 Medical Center North, with RSV mice. OVA/RSV mice had increased IL-23p19 Nashville, TN 37232, USA; mRNA expression in lung homogenates compared with dawn.newcomb@vanderbilt. mock, OVA or RSV mice. Unexpectedly, IL-17A KO OVA/ edu RSV mice had increased AR compared with WT OVA/RSV which viral infections cause asthma exacerbations mice. Furthermore, IL-17A KO OVA/RSV mice had remain unknown. Received 10 July 2012 on September 27, 2021 by guest. Protected copyright. Revised 4 January 2013 increased eosinophils, lymphocytes and IL-13 protein To determine the immunological mechanisms Accepted 30 January 2013 expression in BAL fluid compared with WT OVA/RSV associated with viral-induced asthma exacerbations, mice. we and others have previously developed mouse Conclusions IL-17A negatively regulated AR and models of RSV strain A2 infection during ongoing airway inflammation in OVA/RSV mice. This finding is ovalbumin (OVA)-induced allergic airway inflamma- 56 important because IL-17A has been identified as a tion (OVA/RSV). In our model, 8 days after infec- potential therapeutic target in asthma, and inhibiting tion, OVA/RSV mice had the same AR as OVA mice IL-17A in the setting of virally-induced asthma and both groups were significantly increased com- exacerbations may have adverse consequences. pared with non-allergic uninfected mice (mock) or RSV-infected mice. However, 15 days after RSV challenge, OVA/RSV mice had significantly increased AR compared with OVA mice, in which INTRODUCTION AR had declined over time. This model closely Asthma is characterised by increased lung inflam- mimics the heightened and prolonged AR that mation, airway reactivity (AR) and mucus produc- occurs with virally-induced asthma exacerbations in tion. Viral infections trigger 80–85% of asthma people. Interestingly, RSV strain A2 infection exacerbations in children1 and 44% in adults.2 without allergic airway inflammation did not cause To cite: Newcomb DC, Most of these viral-induced asthma events occur increased AR over mock mice at any time point.5 Boswell MG, Reiss S, et al. fl 3 Thorax Published Online in patients with allergic airway in ammation. Interleukin (IL)-13, a Th2 cytokine, is a central First: [please include Day Respiratory syncytial virus (RSV) is associated mediator of AR and airway mucus production in Month Year] doi:10.1136/ with many wheezing episodes and asthma exacer- allergic airway models. Lung IL-13 protein expres- thoraxjnl-2012-202404 bations.4 However, the exact mechanisms by sion was significantly increased in OVA mice CopyrightNewcomb DC, Articleet al. Thorax author2013;0 :1(or–7. their doi:10.1136/thoraxjnl-2012-202404 employer) 2013. Produced by BMJ Publishing Group Ltd (& BTS) under licence.1 Asthma Thorax: first published as 10.1136/thoraxjnl-2012-202404 on 19 February 2013. Downloaded from compared with mock mice,78but lung IL-13 protein expression was significantly reduced in OVA/RSV mice compared with OVA mice.78These findings suggest that IL-13 was not responsible for increased AR in OVA/RSV mice. However, OVA/RSV mice had a significant increase in lung IL-17A protein expression,8 a cytokine associated with severe asthma.910Based on these findings, we hypothesised that IL-17A mediates increased AR and inflammation that occurs in OVA/RSV mice compared with WT mice. IL-17A is produced primarily by Th17 cells and signals Figure 1 Timeline of experimental protocol for ovalbumin (OVA)/ through a heterodimeric receptor composed of IL-17RA and respiratory syncytial virus (RSV) mice. OVA and OVA/RSV mice were IL-17RC subunits.11 It is associated with autoimmune diseases sensitised with intraperitoneal (ip) injection of OVA complexed with Al(OH) (alum) on day –16. Mock and RSV mice were injected ip with such as multiple sclerosis, rheumatoid arthritis and inflammatory 3 alum on day –16. On days –2 through 5 OVA and OVA/RSV mice were bowel diseases, as well as protection against extracellular patho- 11 12 challenged with 1% OVA (in phosphate buffered saline). On day 0, RSV gens. IL-17A protein expression is also increased in bronch- and OVA/RSV mice were infected with RSV strain A2 and mock and oalveolar lavage (BAL) fluid and bronchial biopsy tissue of OVA mice were challenged with uninfected cell culture supernatants. patients with moderate to severe asthma.910 The role of IL-17A in allergic airway inflammation is conflict- ing. Mice deficient in IL-17RA failed to develop OVA-induced 323–339 (1 μg/ml; Sigma-Aldrich), RSV M2 (127–135) peptide 13 − allergic airway inflammation. One potential reason was the (10 7 M; Biosynthesis) or influenza peptide (Flu 147–155) − inability of IL-17RA knockout (KO) mice to respond to IL-17E (10 7 M) as a non-specific negative control (Biosynthesis). Cell (also known as IL-25) which was required for allergic airway culture supernatants were collected 24 h after stimulation. inflammation and increased IL-13 protein expression, eosinophil 14 recruitment and AR. In the same study, Schnyder and collea- Cytokine measurements gues also reported that exogenous instillation of rmIL-17A Cytokine levels were measured from whole lung homogenates fi during OVA challenge decreased AR and eosinophil in ltra- or BAL fluid by ELISA (R & D Systems). Values below the limit tion.13 IL-17A produced from γδ T cells also protected against 15 of detection were assigned half the value of the lowest detect- AR. However, IL-17A was also reported to be important in able standard. the development of allergic airway inflammation. Adoptive transfer of OVA-specific Th17 cells or OVA-specific Th17 plus Quantitative PCR Th2 cells increased AR in BALB/c mice.16 17 Instillation of Quantitative PCR was conducted for IL-23p19 and GAPDH rmIL-17A into the airways also increased AR in mice with using SYBR green mix (BioRad). Primer sequences were as OVA-induced allergic airway inflammation.18 Taken together, follows: IL-23p19 forward, 50-TGGCTGTGCCTAGGAGTAG these studies show that IL-17A both enhanced and inhibited AR CA-30, reverse, 50-TTCATCCTCTTCTT CTCTTAGTAGATTC in mouse models of allergic airway inflammation. The role of http://thorax.bmj.com/ ATA-30; GAPDH, forward, 50-GGCCCCTCTGGAAAGCTGT IL-17A in viral-induced AR and airway inflammation in the GG-30, reverse, 50-CCCGGCATCGAAGGTGGAAGA-30. setting of underlying allergic inflammation has not been eluci- dated and was the purpose of this study. Our objective was to determine the role of IL-17A in airway inflammation and AR in AR measurements a clinically relevant model of asthma exacerbation in which viral Mice were anaesthetised with pentobarbital sodium (85 mg/kg), infection occurs during ongoing allergic airway inflammation. and a tracheostomy tube was placed and the internal jugular This is vital since therapeutics which inhibit IL-17A currently in vein was cannulated. The mice were then placed in a plethysmo- clinical trials for asthma could have unintended effects on aller- graphy chamber and mechanically ventilated. Lung resistance on September 27, 2021 by guest.
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