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

ABSTRACTAsthma is a heterogeneous disease underlying different medical processes, being the allergic asthma, with an early-onset in childhood, the most common type. In this phenotype, the continuous exposure to allergens produces a Th2-driven airway remodeling process that leads to symptoms and pathophysiological changes in asthma. Strategies as the avoidance of aeroallergen exposure in early life have been tested to prevent asthma, without a clear success. Alongside, several mouse models of aeroallergen challenge have dissected potential homeostatic responses by which environmental microbial stimulation reduces the subsequent allergic inflammation in the offspring. This suggests the onset of underlying preventive mechanisms in the beginning of asthma that have not been fully recognized. In this study, we aimed to evaluate if neonatal LPS-induced stimulus in epithelial host defenses could contribute to the prevent asthma in adult Balb/c mice. For this purpose, we studied the response of bronchiolar club cells (CC) that are situated in the crossroads of the host defense and allergic inflammation, and express specific pro and antiallergic proteins. LPS stimulus in the neonatal life intensified the production of TLR-4, TNFα, and natural anti-allergic products (CCSP and SPD), changes that contributed to prevent asthma triggering in adulthood. At epithelial level, CC skipped the mucous metaplasia, declining the overproduction of mucin via the EGFR pathway and the mice expressed normal breathing patterns in front of OVA challenge. Furthermore, the overexpression of TSLP, an epithelial pro-Th2 cytokine was blunted and normal TSLP and IL-4 levels were found in bronchoalveolar lavage (BAL). Complementing this shift, we also detected lower eosinophilia in BAL while an increase in phagocytes as well as in regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+) was seen, whit an elevation in IL-12 and TNFα secretion. Summarizing, our study pointed to stable asthma-preventive effects promoted by neonatal LPS-stimulation; the main finding was the increase of several anti-Th2 specific proteins at epithelial level, together with an important diminution of pro-Th2 TSLP, conditions that promoted changes in the local immune response with Treg. We thus evidenced several anti-allergic dynamic mechanisms overlying in the epithelium that could be favored in an adequate epidemiological environment