MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis

Abstract

Hypersensitivity pneumonitis is an interstitial lung disease that is characterized by alveolitis, granuloma formation, and in some patients, fibrosis. Using the Saccharopolyspora rectivirgula animal model of Farmer's lung disease, our laboratory has demonstrated that neutrophils play a critical role in IFN-gamma production during the acute phase of the disease. As IFN-gamma is necessary for granuloma formation, it is important to identify the factors that lead to neutrophil recruitment during disease. To begin to identify the pattern recognition receptors (PRRs) that initiate chemokine production, leading to neutrophil recruitment following S. rectivirgula exposure, we examined the role of MyD88 and TLR2. Our results demonstrate that neutrophil recruitment, as measured by flow cytometry and the myeloperoxidase assay, was abolished in the absence of MyD88 following S. rectivirgula exposure. The decrease in neutrophil recruitment was likely a result of a significant decrease in production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine. These results suggest that S. rectivirgula interacts with PRRs that are upstream of the MyD88 pathway to initiate cytokine and chemokine production. In vitro studies suggest that S. rectivirgula can interact with TLR2, and stimulation of adherent cells from TLR2 knockout (KO) mice with S. rectivirgula resulted in a significant decrease in MIP-2 production. However, TLR2 KO mice did not have a reduction in neutrophil recruitment compared with wild-type mice following S. rectivirgula exposure. The results from our studies suggest that one or more PRR(s) upstream of MyD88 are necessary for neutrophil recruitment following S. rectivirgula exposure.