Features of Environmental Dust Exposure Induced Lung Disease Regulated by MyD88 Result in a Prolonged Adaptation Response

Abstract

Environmental organic dust exposures, rich in Toll-like receptor (TLR) agonists, can reduce allergic asthma development, but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein MyD88 is fundamental in the acute inflammatory response to organic dust extract (ODE), yet MyD88’s role in regulating the lung response with repetitive exposures is unknown and could inform future preventative and therapeutic strategies. Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for three weeks and euthanized (repetitive exposure) or rested with no treatments for four weeks (recovery phase) followed by challenge once with saline/ODE. Bronchoalveolar lavage fluid (BALF), lung tissues, and serum were collected. Repetitive ODE exposure-induced neutrophil influx and release of Th1 inflammatory cytokines and chemokines were profoundly reduced in KO mice. In comparison, ODE-induced cellular aggregates, B cells, and mast cell infiltrates and serum IgE levels remained elevated whereas bronchiolar epithelial mucous cell metaplasia was increased in KO animals. Following recovery and then re-challenge with ODE, inflammatory cytokines, but not neutrophil influx, was reduced in WT mice pre-treated with ODE, suggesting an adaptation response. However, the alarmin cytokine IL-33 and anti-inflammatory cytokine IL-10 were significantly increased in the lungs of these same WT mice. Repetitively exposed KO mice lacked responsiveness upon ODE re-challenge. MyD88-dependent signaling is essential in mediating the classic airway inflammatory response to repetitive organic dust exposures, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or generalized IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response.