US soldiers who have served in Iraq show an increased risk for allergic rhinitis and asthma. Soldiers deployed in the Persian Gulf had twice the risk of developing allergic rhinitis as compared to homeland stationed personnel and 1.6 times the risk of developing asthma. Furthermore, the diagnosis of asthma with symptoms after the age of 12 years is an exclusion critierion for military enlistment. While the reason for the increased risk for allergic inflammatoy diseases has not been established, exposure to high levels of dust and other inhaled particles is thought to be the most likely explanation. The ubiquitous environmental allergen, house dust mite (HDM), was found in high levels in the tents of soldiers serving in Iraq and is known to be a major inducer of asthma. It has been estimated that between 50-80% of rhinitis and asthma is due to HDM;however, the mechanisms by which HDM induces and exacerbates asthma are not fully understood. HDM and many other inhaled particulates contain stimulatory structures we have termed allergen- associated molecular patterns (AAMPs) that engage and stimulate innate pattern recognition receptors (PRR). While others have studied the effects of HDM on epithelial and dendritic cells, we have found that HDM directly activates macrophages, a cell that is central in the innate immune system and found in abundance in the lungs and airways. HDM stimulates macrophages to induce the expression of IFN-? and several genes that are characteristic of alternatively activated macrophages (AAM), including chitinase family members, that are strongly associated with allergic disease. Thus, our overall goal in this proposal is to characterize the innate immune sensing systems utilized by HDM that lead to an alternatively activated state of macrophage differentiation. An understanding of this process is clinically important;human asthmatics have elevated numbers of AAM and increased amounts of chitinase proteins in their blood and airways, especially during asthma exacerbations. Furthermore, we have shown that AAM initiate and amplify the symptoms of asthma in a mouse model. The central hypothesis to be tested is that the array of AAMPs found in HDM activate innate signaling pathways that coordinately lead to the expression of AAM genes in macrophages enhancing allergy and asthma.
The specific aims designed to test these hypotheses are 1) to determine the contribution of cell surface sensors in HDM-induced responses, 2) to determine the role of the inflammasome and IL-1 family members in HDM-induced effects, 3) to analyze the contribution of IFN-? to the HDM-induced responses, and 4) to validate the effect of HDM on macrophages by comparing responses in human macrophages isolated from controls or asthmatic veterans. These experiments will be performed in vitro by stimulating macrophages prepared from wild type and gene deficient mice with HDM. We will also analyze the effects of HDM on human macrophages derived from PBMC. Importantly, once we identify an innate sensor and signaling pathway that is necessary for HDM-induced effects on macrophages in vitro, we will analyze the importance of the sensor in macrophage activation and allergic lung inflammation in vivo using a mouse model of HDM-induced asthma. The anticipated outcome of our research is that it will delineate the signaling pathways activated by the ubiquitous environmental allergen HDM that drive expression of AAM genes. This increase in knowledge will have benefit for veterans and the nation because these pathways will likely lead to the identification of new targets for the control of HDM-induced allergic rhinitis and asthma.
The number of people in the United States with asthma has dramatically increased over the past 40 years. Unfortunately, the diagnosis of asthma with symptoms after the age of 12 years is an exclusion critierion for military enlistment. Furthermore, US soldiers who have served in Iraq show an increased risk for allergic rhinitis and asthma. Soldiers deployed in the Persian Gulf had twice the risk of developing allergic rhinitis as compared to homeland stationed personnel and 1.6 times the risk of developing asthma. Exposure to high levels of dust and other inhaled particulates is thought to explain the increased risk. The ubiquitous environmental allergen, house dust mite (HDM), was found in high levels in the tents of soldiers serving in Iraq and is known to be a major inducer of asthma. Our research project will analyze how house dust mite controls the differentiation of macrophages and enhances the symptoms of asthma. Thus, our proposed studies have significant potential to identify novel asthma targets of benefit to veterans and the nation.
|Keegan, Achsah D; Shirey, Kari Ann; Bagdure, Dayanand et al. (2016) Enhanced allergic responsiveness after early childhood infection with respiratory viruses: Are long-lived alternatively activated macrophages the missing link? Pathog Dis 74:|
|Dasgupta, Preeta; Dorsey, Nicolas J; Li, Jiaqi et al. (2016) The adaptor protein insulin receptor substrate 2 inhibits alternative macrophage activation and allergic lung inflammation. Sci Signal 9:ra63|
|Keegan, Achsah D (2015) IL-4 and IL-13: from ""supe"" to nuts. Cytokine 75:1-2|