Dietary saturated fatty acids promote lung myeloid cell inflammasome activation and IL-1β-mediated inflammation in mice and humans

Resident tissue macrophages and monocytes (RTMs) integrate local and systemic signals to coordinate immune cell function at homeostasis and in response to inflammatory stimuli. Obesity-associated metabolic dysfunction drives the development of RTM populations that contribute to disease states in multiple tissues. However, the contribution of specific dietary components to innate immune cell activation and function, as opposed to the effects of obesity per se, is largely unknown. Herein, we studied the mechanisms by which high fat (HF) diets shape lung RTM phenotype and function in the steady state and influence responses to inflammatory insults. We report that during HF diet feeding, lung RTMs accumulate saturated long chain fatty acids (LCFA), specifically stearic acid (SA), and demonstrate features of NLRP3 inflammasome priming and activation. In vivo, increased dietary SA was sufficient to cause neutrophil-predominant lung inflammation in the steady state and exacerbate a model of innate airway inflammation, while increased dietary oleic acid, the monounsaturated counterpart of SA, was sufficient to reduce inflammasome activation in the steady state and attenuate airway inflammation. Importantly, depletion of IL-1β or pharmacologic inhibition of the endonuclease IRE1⍺ protected against SA-induced exacerbated lung inflammation. Finally, we identified a population of lung monocytes with hallmarks of HF diet-induced RTM activation that are present in obese humans with asthma. Together, these results identify a class of dietary lipids that regulate lung RTM phenotype and function in the steady state and modulate the severity of inflammation in the lung.