Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Metabolic pathways such as mitochondrial long-chain fatty acid oxidation (mtLCFAO) in AT2 cells are assumed to aggravate alveolar inflammatory responses in acute lung injury (ALI), but the biological importance of mtLCFAO to AT2 cell function has yet to be extensively defined. Here, we show that individuals with acute respiratory distress syndrome (ARDS) have a significant loss in expression of the mtLCFAO rate limiting enzyme, carnitine palmitoyltransferase 1a (CPT1a) in the alveolar epithelium. In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and upregulates phospholipid synthesis, leading to altered surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deletion of either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as a key immunometabolic response of the AT2 cells to injury and suggests that a loss of mtLCFAO in the alveolar epithelium is an anti-inflammatory response in ARDS.