Neonatal endotoxin stimulation was associated with long- term innate immune markers and an anti-allergic response in bronchiolar epithelium in spite of allergen challenge

Abstract

22Asthma is a heterogeneous disease underlying different medical processes, being the 23 allergic asthma, with an early-onset in childhood, the most common type. In this 24 phenotype, the continuous exposure to allergens produces a Th2-driven airway 25 remodeling process that leads to symptoms and pathophysiological changes in asthma. 26 Strategies as the avoidance of aeroallergen exposure in early life have been tested to 27 prevent asthma, without a clear success. Alongside, several mouse models of 28 aeroallergen challenge have dissected potential homeostatic responses by which 29 environmental microbial stimulation reduces the subsequent allergic inflammation in 30 the offspring. This suggests the onset of underlying preventive mechanisms in the 31 beginning of asthma that have not been fully recognized. In this study, we aimed to 32 evaluate if neonatal LPS-induced stimulus in epithelial host defenses could contribute to 33 the prevent asthma in adult Balb/c mice. For this purpose, we studied the response of 34 bronchiolar club cells (CC) that are situated in the crossroads of the host defense and 35 allergic inflammation, and express specific pro and antiallergic proteins. LPS stimulus 36 in the neonatal life intensified the production of TLR-4, TNFα, and natural anti-allergic 37 products (CCSP and SPD), changes that contributed to prevent asthma triggering in 38 adulthood. At epithelial level, CC skipped the mucous metaplasia, declining the 39 overproduction of mucin via the EGFR pathway and the mice expressed normal 40 breathing patterns in front of OVA challenge. Furthermore, the overexpression of 41 TSLP, an epithelial pro-Th2 cytokine was blunted and normal TSLP and IL-4 levels 42 were found in bronchoalveolar lavage (BAL). Complementing this shift, we also 43 detected lower eosinophilia in BAL while an increase in phagocytes as well as in 44 regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+) was seen, whit an elevation 45 in IL-12 and TNFα secretion. Summarizing, our study pointed to stable asthma-3 46 preventive effects promoted by neonatal LPS-stimulation; the main finding was the 47 increase of several anti-Th2 specific proteins at epithelial level, together with an 48 important diminution of pro-Th2 TSLP, conditions that promoted changes in the local 49 immune response with Treg. We thus evidenced several anti-allergic dynamic 50 mechanisms overlying in the epithelium that could be favored in an adequate 51 epidemiological environment 52 KEY WORDS: 53 Club cell, asthma, pulmonary host defense, antiallergic proteins 54 . 4 55 INTRODUCTION 56Asthma is a heterogeneous disease with diverse underlying processes and many 57 clinical expressions. The most common phenotype is the allergic asthma that has an 58 early-onset in childhood. This phenotype is associated with a family history of allergic 59 diseases, and is characterized by chronic airways inflammation, with activated mast 60 cells, increased numbers of eosinophils, T cells, natural killer T cells, and CD4+ T 61 helper (Th) 2 cells that rel...