Abstract
Inhalation of organic dusts within agriculture environments contributes to the development and/or severity of airway diseases, including asthma and chronic bronchitis. MyD88 KO (knockout) mice are nearly completely protected against the inflammatory and bronchoconstriction effects induced by acute organic dust extract (ODE) treatments. However, the contribution of MyD88 in lung epithelial cell responses remains unclear. In the present study, we first addressed whether ODE-induced changes in epithelial cell responses were MyD88-dependent by quantitating ciliary beat frequency and cell migration following wounding by electric cell-substrate impedance sensing. We demonstrate that the normative ciliary beat slowing response to ODE is delayed in MyD88 KO tracheal epithelial cells as compared to wild type (WT) control. Similarly, the normative ODE-induced slowing of cell migration in response to wound repair was aberrant in MyD88 KO cells. Next, we created MyD88 bone marrow chimera mice to investigate the relative contribution of MyD88-dependent signaling in lung resident (predominately epithelial cells) versus hematopoietic cells. Importantly, we demonstrate that ODE-induced airway hyperresponsiveness is MyD88-dependent in lung resident cells, whereas MyD88 action in hematopoietic cells is mainly responsible for ODE-induced TNF-α release. MyD88 signaling in lung resident and hematopoietic cells are necessary for ODE-induced IL-6 and neutrophil chemoattractant (CXCL1 and CXCL2) release and neutrophil influx. Collectively, these findings underscore an important role for MyD88 in lung resident cells for regulating ciliary motility, wound repair and inflammatory responses to ODE, and moreover, show that airway hyperresponsiveness appears uncoupled from airway inflammatory consequences to organic dust challenge in terms of MyD88 involvement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0272-9) contains supplementary material, which is available to authorized users.
Highlights
Inhalation of organic dusts can result in several inflammatory respiratory diseases, such as asthma, chronic bronchitis, obstructive lung disease, and hypersensitivity pneumonitis, in agriculture-exposed workers [1]
We have previously demonstrated that organic dust extract (ODE) slows ciliary beat frequency (CBF) [14], and these findings were confirmed in wild type (WT) mice (Fig. 1a)
The normative ODE-induced CBF slowing response was absent in myeloid differentiation factor 88 (MyD88) KO epithelial cells at 1 and 6 h post-exposure (N = 6 independent experiments performed in triplicate; Fig. 1a)
Summary
Inhalation of organic dusts can result in several inflammatory respiratory diseases, such as asthma, chronic bronchitis, obstructive lung disease, and hypersensitivity pneumonitis, in agriculture-exposed workers [1]. Acute organic dust extract (ODE)-induced AHR in conjunction with neutrophil influx and release of inflammatory cytokines/chemokines into the bronchoalveolar space, but not lung parenchyma, was nearly completely abrogated in MyD88 knock-out (KO) mice [4]. In comparison studies, we did not find a role for IL-1R, and only a limited role for IL-18R, signaling pathway in mediating acute ODE-induced airway inflammatory responses [4]. Based on these findings, we had speculated that MyD88-dependent signaling in lung resident cells, mainly epithelial cells, was mediating airway inflammatory and pulmonary function consequences to acute ODE challenge. The importance of MyD88 in epithelial cells and the relative contribution of MyD88 in the lung resident (i.e. epithelial) cell compartment as compared to leukocytes following organic dust exposures remained undefined
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