Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma

Abstract

Atopic asthma is a chronic allergic disease that involves T-helper type 2 (Th2)-inflammation and airway remodeling. Bronchiolar club cells (CC) and alveolar macrophages (AM) are sentinel cells of airway barrier against inhaled injuries, where allergy induces mucous metaplasia of CC and the alternative activation of AM, which compromise host defense mechanisms and amplify Th2-inflammation. As there is evidence that high levels of environmental endotoxin modulates asthma, the goal of this study was to evaluate if the activation of local host defenses by Lipopolysaccharide (LPS) previous to allergy development can contribute to preserving CC and AM protective phenotypes. Endotoxin stimulus before allergen exposition reduced hallmarks of allergic inflammation including eosinophil influx, Interleukin-4 and airway hyperreactivity, while the T-helper type 1 related cytokines IL-12 and Interferon-γ were enhanced. This response was accompanied by the preservation of the normal CC phenotype and the anti-allergic proteins Club Cell Secretory Protein (CCSP) and Surfactant-D, thereby leading to lower levels of CC metaplasia and preventing the increase of the pro-Th2 cytokine Thymic stromal lymphopoietin. In addition, classically activated alveolar macrophages expressing nitric oxide were promoted over the alternatively activated ones that expressed arginase-1. We verified that LPS induced a long-term overexpression of CCSP and the innate immune markers Toll-like receptor 4, and Tumor Necrosis Factor-α, changes that were preserved in spite of the allergen challenge. These results demonstrate that LPS pre-exposition modifies the local bronchioalveolar microenvironment by inducing natural anti-allergic mechanisms while reducing local factors that drive Th2 type responses, thus modulating allergic inflammation.

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

“…As was shown before (55), the OVA-allergic inflammation incited mucous cell metaplasia in the bronchiolar Club cell via EGFR signaling. In this way, Figure 3 shows an increased number of mucous secreting cells (AB-PAS panel in Fig 3a and Fig.…”

“…Next, we analyzed whether the mucous metaplasia prevention by neonatal LPS treatment correlated with changes in the expression of epithelial host defense mediators, mainly CCSP and SP-D. As it was described (55), OVA-allergic inflammation induced a diminution in the imunoreactivity of CCSP and SP-D in CC of PBSn/OVA group when compared to its control group (CCSP and SP-D panels in Fig 5a). Meanwhile for both LPSn and LPSn/OVA groups, a strong CCSP and SP-D immunolabelling was observed (Fig 5a).…”

“…Recently, we determined that the pre-treatment of adult mice with LPS before an allergic inflammation partially prevented CCSP and SP-D reduction in CC, and the increase of IL-4 levels and airways hyperresponsiveness (55). However, in the present work we demonstrate that when endotoxin treatment is performed in neonatal life it achieved a more extensive asthma prevention in adulthood.…”

“…In consequence, the loss of anti-allergic products in CC and alveolar adult mice macrophages were prevented. We observed a reduction of eosinophil influx, Interleukin-4 levels and airway hyperreactivity, while the T-helper type 1 related cytokines IL-12 and Interferon-g were enhanced (55). Considering early life as a better window of opportunity for triggering an appropriate maturation of innate immunity.…”

Interaction between allergic asthma and atherosclerosis

“…61 Previous studies have demonstrated that lipopolysaccharide (LPS) pre-exposition modified the local bronchioalveolar microenvironment by promoting features of M1 macrophages that express nitric oxide, while avoiding M2 macrophage expression of arginase-1 and reducing local factors that drive Th2 type responses, thereby suppressing allergic inflammation. 62 By quantifying the lung macrophage populations in two established murine models of allergic and non-allergic lung inflammation, data showed that M2 macrophages predominantly localized in the lungs in allergic asthma, while M1-dominant macrophages were more prevalent in non-allergic inflammation, which may contribute to Th1/Th17 responses via the transcription factor interferon-regulatory factor 5 (IRF5). Thus, interfering with this polarization may potentially lead to the treatment of different types of lung inflammation.…”