Mechanisms of allergy and clinical immunology
Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A

https://doi.org/10.1016/j.jaci.2013.11.014Get rights and content

Background

β-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described in vitro.

Objective

We sought to elucidate the molecular mechanisms by which β-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B–exacerbated allergic airways disease (AAD).

Methods

Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]).

Results

Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor κB subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A in vitro isolated from human airway epithelial cells.

Conclusions

Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits.

Section snippets

Methods

For more detailed methods, see the Methods section in this article's Online Repository at www.jacionline.org.

Systemic salmeterol suppresses HDM-induced AHR and inflammation but not numbers of PAS-positive cells

We administered salmeterol or vehicle control intraperitoneally 24 hours before and during the challenge phase in a mouse model of HDM-induced AAD (see Fig E1, A). Data collection was performed 24 hours after the last salmeterol administration to account for possible bronchodilator effects influencing airways resistance. This was based on the documented duration of action of salmeterol in human subjects,29 as well as our own data from time course studies in naive mice showing protective effects

Discussion

Using a well-characterized model of HDM-induced AAD,26, 27 we observed suppression of AHR, as well as reduced eosinophilic airways inflammation, caused by systemic and local salmeterol treatment, whereas blood eosinophil levels mildly increased. This suggests that the anti-inflammatory effect of salmeterol might be associated with impaired eosinophilic chemotaxis rather than proliferation or maturation. This was supported by reduced levels of CCL11, which is crucial for eosinophil tissue homing,

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  • Cited by (0)

    Supported by the National Health Medical Research Council (NH&MRC; G1000314 to J.M. and N.V.) and an NH&MRC Health Professional Research Fellowship (G0186769 to J.M.). S.L.J. was supported by a Chair from Asthma UK (CH1155). This work was supported in part by MRC Centre Grant G1000758 and ERC FP7 Advanced Grant 233015 (to S.L.J.).

    Disclosure of potential conflict of interest: N. Verrills has received research support from the NH&MRC (grant no. G1000314). S. L. Johnston has received research support from a Chair from Asthma UK (Ch1155), the Medical Research Council (grant no. G1000758), and the European Research Council (FP7 advanced grant G233015); has received consultancy fees from Centocor, Sanofi Pasteur, Synairgen, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Grünenthal, and Novartis; has patents planned, pending, or issued (UK patent application no. 02 167 29.4 and International patent application no. PCT/EP2003/007939; UK patent application no. GB 0405634.7; UK patent application no. 0518425.4); and has stock/stock options in Synairgen. J. Mattes has received research support from the National Health and Medical Research Council (NH&MRC; grant no. G1000314) and an NH&MRC Health Professional Research Fellowship (GO186769). The rest of the authors declare that they have no relevant conflicts of interest.

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