Bacillus-derived poly-gamma-glutamic acid attenuates allergic airway inflammation through a Toll-like receptor-4-dependent pathway in a murine model of asthma.

摘要

BACKGROUND: Asthma is an inflammatory disease of the airways that is mediated by Th2 responses. Poly-gamma-glutamic acid (gamma-PGA) is an extracellular polymeric compound that is synthesized by Bacillus cells. Previously, we found that gamma-PGA promoted Th1 cell development in a manner dependent on antigen-presenting cells, but inhibited Th2 cell development. OBJECTIVE: To investigate the effect of gamma-PGA on dendritic cells (DCs), and its potential for treating Th2-mediated allergic asthma. METHODS: Wild-type, Toll-like receptor (TLR)-2 deficient, and TLR-4-defective mice were used. DCs derived from the bone marrow and extracted from the lung were stimulated with gamma-PGA and assayed for the expression of signalling molecules, costimulatory molecules, and cytokines. Mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. They were repeatedly injected intranasally with gamma-PGA before and during the challenge period, and inflammation and structural remodelling of the airways were examined. RESULTS: gamma-PGA selectively signalled conventional DCs to activate NF-kappaB and mitogen-activated protein kinase, leading to the up-regulation of CD86, CD40, and IL-12, but not IL-10 and IL-6. These effects of gamma-PGA were dependent on TLR-4 and independent of TLR-2. Importantly, the intranasal administration of gamma-PGA to OVA-sensitized/challenged mice reduced the airway hyperresponsiveness and allergic inflammation such as leucocyte influx, goblet cell hyperplasia, eosinophilia, and Th2 cytokine production. In addition to lowered IgE titres, the treatment of mice with gamma-PGA significantly reduced the multiplication and Th2 polarization of mediastinal lymph node T cells upon allergen-specific restimulation. These anti-asthmatic effects of gamma-PGA were also abolished in TLR-4-defective mice. CONCLUSIONS AND CLINICAL RELEVANCE: Our data indicate that gamma-PGA activates DCs to favour Th1 cell induction through a TLR-4-dependent pathway and alleviates pathologic symptoms in a Th2-biased asthmatic model. These findings highlight the potential of gamma-PGA for the treatment of asthma and other allergic disease in which Th2 polarization plays an important role.