"The effects of obesity on lung macrophage metabolism and function"

Sam McCright and David Hill

Obesity is a risk factor for the development of asthma, and obesity-associated asthma (OAA) is more severe and more difficult to treat than atopic asthma. Lung macrophages have been implicated in the regulation of OAA immunopathology, however, the mechanisms by which obesity alters lung macrophages are not well understood. As OAA is often refractory to conventional treatments for atopic asthma, an improved understanding of the contribution of lung macrophages to OAA immunopathology will facilitate the development of targeted therapies for this asthma endotype.

To understand the effects of obesity on lung macrophages and determine the contribution of lung macrophages to OAA-like inflammation, we compared the cellular phenotype, transcriptome, and lipidome of lung macrophages from lean and obese mice. Analysis by flow cytometry found that obesity causes expansion of lung interstitial macrophages with increased intracellular lipid and cell-surface expression of the metabolic activation marker CD9. Additionally, obesity increases lung macrophage expression of lipid metabolism genes (e.g., Plin2, Lpl, Lipa). Lipidomic analysis revealed increased abundance of specific long chain fatty acids (LCFAs) in macrophages isolated from the obese lung, and in vitro studies demonstrated that these LCFAs are sufficient to induce both cellular-metabolic and inflammatory aspects of obesity-associated macrophage activation. Ongoing studies will investigate the molecular mechanisms by which LCFAs and other lipids alter macrophage metabolism and function and will determine the contribution of obesity-associated macrophages to a model of OAA. Taken together, this work raises the possibility that modulating lung macrophage cellular metabolic pathways may represent a novel avenue for the development of therapies for this severe disease.