The effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent

Davies, Elizabeth, Wandel, Marieke, Kelly, Joanne, Freda Carmichael, Holgate, Stephen T, Whitsett, Jeffrey A., Davies, Donna E and Haitchi, Hans Michael (2018) The effect of soluble ADAM33 on allergic airway inflammation in early life is age dependent. Thorax, 73 (Suppl 4), A18, [73(Suppl 4):A1-A282]. (doi:10.1136/thorax-2018-212555.35).

Abstract

Introduction: most asthma has its origin in early life and probably involves gene-environment interactions. The asthma susceptibility gene ADAM33 is associated with bronchial hyperresponsiveness (BHR) and reduced lung function in young children. It encodes a membrane-anchored metalloprotease, which is shed as a soluble protein (sADAM33) whose levels are increased in asthma. We have previously shown that sADAM33, promotes airway remodelling and augments allergic airway inflammation in juvenile mice (Davies ER et al, JCI Insight 2016). This might be initiated by ADAM33 induced innate lymphocytes (Kelly JFC et al, Thorax 2017). The aim of this work was to evaluate the effect of sADAM33 on the allergic airway responses of neonates.

Methods: human sADAM33 was induced in lungs of double transgenic (Ccsp/ADAM33) (dTg) mice from in utero up to 4 weeks post-partum. dTg mice or single transgenic (sTg) controls were challenged with house dust mite extract (HDM) 3 times a week for 2 weeks from 3 or 14 days post-partum. BHR and inflammation were quantified. Lung tissue was analysed by RT-qPCR and immunohistochemistry (IHC).

Results: after HDM challenge from day 3, Type 2-responsive genes Il-5, Ccl11/Eotaxin and Muc5ac were significantly increased. Whilst an increase in BHR was observed after HDM challenge, there was no significant difference between sADAM33-expressing and control mice. In contrast, when challenged from day 14, sADAM33-expressing mice had a more robust eosinophilic inflammatory response in the bronchoalveolar lavage fluid with increased Il-5 and Ccl11/Eotaxin mRNA expression compared to littermate controls. This was also associated with increased Acta2 mRNA expression and BHR.

Conclusion: these data indicate that sADAM33 does not augment allergic responses in neonatal mice as robustly as in older mice. This suggests that the immune microenvironment in neonates is not sufficiently mature to respond to the pro-allergic effects of sADAM33 that may induce innate lymphocytes to make the airways more susceptible to allergic airway inflammation.

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Contributors

Author: Elizabeth Davies

Author: Donna E Davies

Author: Hans Michael Haitchi

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