TLR2 activation causes tachyphylaxis to β2-agonists in vitro and ex vivo: modelling bacterial exacerbation

Background: Asthma is a widespread chronic health problem exacerbated by common viral and bacterial infections. Further research is required to understand how infection worsens asthma control in order to advance therapeutic options in the future. Recent research has revealed that beta(2)-adrenergic receptor (beta(2)-AR) agonists lose bronchodilatory efficacy because the receptor-mediated molecular pathways responsible for their beneficial actions are desensitized by infection. To date, most studies have focussed on viral infection, leaving the impact of bacterial infection on (beta(2)-AR desensitization relatively under-investigated. We address this in this study. Methods and Results: Utilizing an in vitro model of bacterial exacerbation in airway smooth muscle (ASM) cells, we show that activation of toll-like receptor 2 (TLR2; mimicking bacterial infection) in the presence of an inflammatory stimulus leads to beta(2)-AR desensitization. This occurs via TLR2-dependent upregulation of cyclooxygenase 2 (COX-2) mRNA expression and increased secretion of PGE(2). Importantly, PGE(2) causes heterologous beta(2)-AR desensitization and reduces cAMP production in response to short-acting (salbutamol) and long-acting (formoterol) beta(2)-agonists. Thus, bacterial infectious stimuli act in a PGE(2)-dependent manner to severely curtail the beneficial actions of beta(2)-agonists. The impact of beta(2)-AR desensitization is demonstrated by reduced gene expression of the critical anti-inflammatory molecule MKP-1 in response to beta(2)-agonists, as well as impaired bronchodilation in a mouse lung slices. Conclusions: Taken together, our results show that, like viruses, bacteria induce prostanoid-dependent beta(2)-AR desensitization on ASM cells. Notably, COX-2 inhibition with the specific inhibitor celecoxib represses PGE(2) secretion, presenting a feasible pharmacological option for treatment of infectious exacerbation in asthma in the future.