Pulmonary Innate Immune Modulation in the Pathogenesis of Allergic Asthma.

Abstract

Recent studies have shown that the innate immune response plays a significant role in the adaptive immune response in asthma. However, controversy exists regarding whether innate immune activating substances such as particulate matter, and bacterial components such as lipopolysaccharide (LPS) protect against or potentiate allergic diseases. Our studies first sought to determine whether LPS at the challenge phase of asthma affects the adaptive immune response. Because LPS is ubiquitously present in ambient air, we determined whether repeated LPS inhalation alone could modulate the pulmonary immune environment, thereby affecting the onset and progression of asthma. Because increasing emphasis is being placed in removal of bacterial components from the home as a means of attenuating asthma severity, we determined the affect of LPS during the challenge phase of asthma in a clinically relevant model. Asthma-like pulmonary inflammation was induced by sensitization to cockroach allergens, and challenge with a house dust extract (HDE) collected from the home of an asthmatic child. Depletion of LPS from the HDE resulted in attenuation of IgE, and augmented Th1 and Th2 cytokine production in the lung. The LPS-depleted HDE also exacerbated airways hyper-reactivity (AHR), suggesting that LPS removal from the home environment does not protect against the asthmatic phenotype. We sought to determine whether repeated inhalation of LPS would cause a transient state of refractoriness to further LPS challenge, termed LPS tolerance. Mice receiving two LPS exposures were protected from excessive inflammation through attenuated TNFα and IL-6, but maintained neutrophil recruitment. We then developed a more clinically relevant model of chronic LPS inhalation and found selective suppression of TNFα, but augmented IL-6. LPS tolerance also protected from AHR through the mechanism of reduced muscarinic receptor expression. We then determined whether LPS tolerance can affect allergic asthma. Induction of LPS tolerance immediately prior to allergen sensitization resulted in protection from airway eosinophilia, IgE production and AHR in response to allergen challenge. These findings suggest that LPS inhalation causes local immune modulation that can affect both the sensitization and challenge phases of asthma. Further, we demonstrated that transient innate immune modulation, can have lasting effects on adaptive immunity.