House dust extracts elicit Toll-like receptor-dependent dendritic cell responses

Background: Laboratory and epidemiological studies have provided indirect but compelling evidence that Toll-like receptors (TLRs) play an important role in innate host responsiveness to ambient immunostimulatory factors. However, little direct evidence exists. Objective: To determine whether house dust extracts activate dendritic cells by TLR-dependent mechanisms. Methods: In initial studies, bone marrow-derived dendritic cells were cultured with sterile house dust extracts, and cytokine production and costimulatory molecule expression were evaluated. In additional experiments, the TLR dependence of these responses was assessed. Results: House dust extract-activated bone marrow-derived dendritic cells were found to produce IL-6 and IL-12 in a concentration-dependent manner and to increase their expression of CD40, CD80, CD86, and MHC class II molecules. Furthermore, correlations were seen between the relative bioactivities of house dust extracts and their endotoxin levels. Finally, bone marrow-derived dendritic cells from TLR (2, 49 and 9)-deficient mice all demonstrated attenuated responses, and MyD88 deficient bone marrow-derived dendritic cells were almost completely nonresponsive to house dust extracts. Conclusion: These investigations provide direct evidence that TLR signaling pathways play a central role in at least a subset of dendritic cell responses to noninfectious factors ubiquitous in living environments.