Impact of Obesity on Lung Macrophage Metabolism and Inflammation

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PROJECT SUMMARY/ABSTRACT Obesity increases the risk of developing asthma in children and adults, and obesity-associated asthma (OAA) is often more severe and more difficult to treat than atopic asthma. These poor clinical outcomes may stem from OAA’s distinct immunopathology that includes differences in how lung immune cells respond to inflammatory stimuli and a heterogeneous but neutrophil-predominant lung inflammation. Our limited understanding of how obesity alters lung innate immune cell responses to inflammatory stimuli hinders the development of novel preventative and therapeutic approaches for OAA. Obesity causes lipid deposition in the lung and lipid accumulation in lung tissue resident macrophages (TRMs). These processes may contribute to OAA immunopathology as TRMs are both intimately involved in asthma pathogenesis and sensitive to immunometabolic reprogramming during obesity. Despite this, we do not know if lung TRMs adopt distinct immunometabolic and functional programs as a result of obesity, or if obesity-associated lung TRMs contribute to OAA. To begin to address this knowledge gap, we have performed preliminary studies of lung TRMs in lean and obese mice. We observe lipid-laden TRMs that express proteins characteristic of immunometabolic reprogramming and inflammatory activation in the lungs of obese mice. Using minimally biased lipidomics and in vitro culture techniques, we have identified the fatty acid stearate as a key metabolic signal that may influence lung TRM inflammatory functions during obesity. Finally, we find that obesity and stearate cause activation of the TRM inflammasome—an outcome that is observed in non-lung TRMs during obesity and may contribute to OAA immunopathology. Based on these data, I hypothesize that stearate activates an immunometabolic functional program in lung TRMs that causes exaggerated inflammasome-mediated inflammation in response to innate stimuli. The objectives of this grant are to: (1) identify the lipid signals, cellular metabolic pathways, and inflammatory consequences of obesity-associated lung TRM immunometabolic reprogramming in mice and humans and (2) test the contribution of the TRM inflammasome to OAA-like innate lung inflammation. To attain these objectives, we have developed or obtained novel mouse model systems and established unique collaborations that will allow us to mechanistically interrogate obesity-associated immunometabolic reprogramming of lung TRMs in mice, and translate our observations to pediatric and adult subjects. Doing so will identify molecules and pathways that can be targeted by future OAA-specific therapeutics, and inform studies of other obesity-associated inflammatory lung diseases.