Neonatal endotoxin stimulation is associated with a long-term bronchiolar epithelialexpression of innate immune and anti-allergic markers that attenuates the allergic response.

Luciana Noemi García,Cristina Alicia Maldonado,Juan Pablo Nicola,Carolina Leimgruber,Amado Alfredo Quintar,Svetlana P. Chapoval

doi:10.1371/journal.pone.0226233

Abstract

Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.

Highlights

Asthma is a heterogeneous disease with diverse underlying processes and many clinical expressions
IL-4 and TSLP, both associated with Th2 inflammation, exhibited normal levels in the Bronchoalveolar lavage (BAL) of LPS pre-treated mice in spite of the allergen-challenge, while they were significantly higher in PBSn/OVA group (Fig 2C and 2D respectively)
In the present work we demonstrate that neonatal LPS treatment triggers anti-allergic secretory products of the local airway epithelium that persist into adulthood

Summary

Introduction

Asthma is a heterogeneous disease with diverse underlying processes and many clinical expressions. The most common phenotype is allergic asthma, which has an early-onset in childhood and it is associated with a familiar history of allergic diseases. It is characterized by chronic airway inflammation, with activated mast cells and an increased number of eosinophils, T cells, natural killer T cells, and CD4+ Th2 cells that release interleukin IL-4, IL-13, and IL-5. IgE-secreting B cells are induced during the asthmatic process [1, 2] In this phenotype, the continuous exposure to allergens produces several consequences in the structure and function of the airways, with the establishment of a remodeling process including mucus hypersecretion, smooth muscle hyperplasia, subepithelial fibrosis, blood vessel proliferation and the infiltration of inflammatory cells [3]. The avoidance of airborne allergen exposure in early life has been tested in randomized clinical trials, it has not been fully successful in preventing asthma development, suggesting that there are underlying mechanisms that have not yet been completely identified [4, 5]

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