Characterizing the lung-brain axis inflammatory response to agriculture dust and utilizing aspirin-triggered Resolvin D1 as a novel therapeutic

Abstract

Occupational exposure to agriculture dust is strongly linked to the development of chronic pulmonary diseases such as asthma and chronic obstructive pulmonary disease (COPD). The organic dust inhaled in agricultural settings, known as organic dust exposure (ODE), contains high concentrations of immunogenic compounds that lead to immune-mediated chronic lung disease. These pulmonary inflammatory responses to agriculture dust exposure have been extensively characterized, however there is emerging evidence that agriculture dust exposure increases workers' risk for the development of dementia and other neurological disorders. Occupational agriculture dust exposure has been strongly linked to an increased risk of developing dementia and COPD patients experience high rates of memory loss, confusion, depression, and anxiety symptoms. Given this new evidence, we aimed to characterize the neuroinflammatory response to agriculture dust in vitro in cultured microglia and in vivo in mouse models of repetitive agriculture dust exposure. We also evaluated the behavioral outcomes in mice exposed to agriculture dust to link the exposure with reported patient outcomes. There are additional risk factors that have been identified in patients with ODE, one of which is the production of the cytokine interleukin-22 (IL-22), which has been shown to have various functions in pulmonary disease. Some models have demonstrated that IL-22 is elevated in certain disease states and may contribute to susceptibility to secondary exposures, while other models have shown that IL-22 knock-out mouse models experience more severe disease states. We aimed to understand the link between IL-22 and neurological inflammation in an ODE mouse model. Both COPD and dementia are progressive and fatal diseases with limited effective therapies. The development of novel therapeutics to treat these diseases is urgently needed to address these patients' needs. Omega-3 fatty acid metabolites, such as Aspirin-Triggered Resolvin D1 (AT-RvD1) have shown efficacy in reducing inflammation in models of ODE and other inflammatory exposures. We aimed to evaluate the efficacy of AT-RvD1 as a novel therapeutic for the reduction of pulmonary and neurological inflammation elicited by agriculture dust exposure. We aimed to accomplish this through in vitro alveolar macrophage culture and an in vivo repetitive ODE, AT-RvD1 treatment mouse model. We also aimed to determine the role of IL-22 in agriculture dust-induced pulmonary and neurological inflammation utilizing an IL-22 knock-out mouse model of repetitive ODE and AT-RvD1 treatment. Through our investigations, we observed that ODE in macrophages and microglia produce a strong immune response characterized by the secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) and that co-treatment with AT-RvD1 significantly reduces its production. In our in vivo mouse models, we determined that exposure to agriculture dust produced increased numbers of microglia and astrocytes, confirming our hypothesis that agriculture dust exposure leads to neuroinflammation. We also found that AT-RvD1 treatment in these animals reduced the number of microglia and astrocytes. Additionally, we found that knock-out of IL-22 produced increased inflammation compared to wildtype controls and that AT-RvD1 treatment significantly reduced this inflammation. Our behavioral assessment of mice exposed to agriculture dust revealed limited changes in anxiety and memory, warranting further investigation into the effects of ODE on animal behavior. Overall, our investigations revealed that exposure to agricultural dust leads to neurological inflammation in the form of microglia an astrocyte proliferation and pro-inflammatory cytokine production, that IL-22 plays an important role in the regulation of these inflammatory processes, and that AT-RvD1 may be an effective novel therapeutic for agricultural dust exposure-induced inflammatory diseases.