Eosinophil and airway nerve interactions in asthma

Abstract

Airway eosinophils are increased in asthma and are especially abundant around airway nerves. Nerves control bronchoconstiction and in asthma, airway hyperreactivity (where airways contract excessively to inhaled stimuli) develops when eosinophils alter both parasympathetic and sensory nerve function. Eosinophils release major basic protein, which is an antagonist of inhibitory M₂ muscarinic receptors on parasympathetic nerves. Loss of M₂ receptor inhibition potentiates parasympathetic nerve-mediated bronchoconstriction. Eosinophils also increase sensory nerve responsiveness by lowering neurons' activation threshold, stimulating nerve growth, and altering neuropeptide expression. Since sensory nerves activate parasympathetic nerves via a central neuronal reflex, eosinophils' effects on both sensory and parasympathetic nerves potentiate bronchoconstriction. This review explores recent insights into mechanisms and effects of eosinophil and airway nerve interactions in asthma.

Keywords: asthma; eosinophil; major basic protein; parasympathetic nerve; sensory nerve.

FIGURE 1. Sensory and parasympathetic nerves form a complex network in the airways.

(A) Optically cleared mouse lungs labeled with neuronal marker PGP9.5. Images obtained by confocal microscopy. (B and C) Magnified images of nerves along airways and a cluster of nerve cell bodies (ganglia; B middle image). Reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic Society, from Scott et al.

FIGURE 2. Eosinophils cause airway hyperreactivity by altering sensory and parasympathetic nerve function.

Parasympathetic nerves release ACh that activates M₃ muscarinic receptors to induce bronchoconstriction. ACh simultaneously activates presynaptic inhibitory M₂ muscarinic receptors, which reduce further ACh release and serve as an auto-inhibitory feedback mechanism. Sensory nerves can also trigger bronchoconstriction by activating parasympathetic nerves via a central neuronal reflex pathway. In asthma, eosinophils are recruited to nerves by eotaxin-1 and release major basic protein (MBP) that is a parasympathetic nerve M₂ receptor antagonist. Loss of M₂ receptors’ inhibitory feedback results in excessive ACh release and increased bronchoconstriction. Eosinophils affect sensory nerve function as well by inducing nerve growth and increasing sensory neuropeptides such as substance P, which results in increased bronchoconstriction