An Autophagy Modulator Peptide Prevents Lung Function Decrease and Corrects Established Inflammation in Murine Models of Airway Allergy.

Nicolas Schall,Nathalie Petit-Demoulière,François Daubeuf,Sylviane Muller,Nelly Frossard

doi:10.3390/cells10092468

Abstract

The involvement of autophagy and its dysfunction in asthma is still poorly documented. By using a murine model of chronic house dust mite (HDM)-induced airway inflammation, we tested the expression of several autophagy markers in the lung and spleen of asthma-like animals. Compared to control mice, in HDM-sensitized and challenged mice, the expression of sequestosome-1/p62, a multifunctional adaptor protein that plays an important role in the autophagy machinery, was raised in the splenocytes. In contrast, its expression was decreased in the neutrophils recovered from the bronchoalveolar fluid, indicating that autophagy was independently regulated in these two compartments. In a strategy of drug repositioning, we treated allergen-sensitized mice with the therapeutic peptide P140 known to target chaperone-mediated autophagy. A single intravenous administration of P140 in these mice resulted in a significant reduction in airway resistance and elastance, and a reduction in the number of neutrophils and eosinophils present in the bronchoalveolar fluid. It corrected the autophagic alteration without showing any suppressive effect in the production of IgG1 and IgE. Collectively, these findings show that autophagy processes are altered in allergic airway inflammation. This cellular pathway may represent a potential therapeutic target for treating selected patients with asthma.

Highlights

Dust mite represents a major source of allergen in house dust and appears as a key trigger of allergic respiratory disease [1,2], with Dermatophagoides pteronyssinus as the main species [2]
In the present study conducted in two independent mouse models of allergen-induced airway inflammation, we explored the therapeutic potential of a peptide called P140, known in vitro and in vivo to selectively target chaperone-mediated autophagy (CMA)
Based on our previous findings showing that P140 peptide significantly delays the inflammatory manifestations and mortality in several models of inflammatory autoimmune diseases, we first employed this peptide in an acute model of hypereosinophilic airway inflammation in mice, using OVA as the allergen [44]

Summary

Introduction

Dust mite represents a major source of allergen in house dust and appears as a key trigger of allergic respiratory disease [1,2], with Dermatophagoides pteronyssinus as the main species [2]. Der p 1, a cysteine protease, and Der p 2, a lipopolysaccharide (LPS)-binding protein, are considered as the most potent house dust mite (HDM) allergens. They are abundant in the bodies and fæces of mites, and immunoglobulin (Ig)E reactivity can reach up to 80–90% in HDM-allergic patients. The major allergenic effects in HDM allergy result from both adaptive immune mechanisms through CD4+ Th2 cells that induce and drive. IgE-dependent allergic responses, and innate immune reactions. Current therapeutic options involve allergen avoidance, pharmacological intervention (e.g., anti-histamine, corticosteroids, therapeutic antibodies to IgE, IL-4/IL-13 receptor, IL-5, IL-5R, thymic stromal lymphopoietin) and allergen immunotherapy [3,4,5,6,7,8,9]

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Conclusion