Alveolar macrophages: guardians of the alveolar lipid galaxy

As the primary guardians at the air-surface interface, the functional profile of alveolar macrophages (AM) is wide-ranging from establishment of the alveolar niche, homeostatic maintenance of surfactant levels, to pathogen clearance and resolution and repair processes. Alveolar lipid homeostasis is disturbed in chronic lung diseases and contributes to disease pathogenesis through extracellular localization in the alveolar lumen or intracellular accumulation in AM. This review aims to provide a focused overview of the state of knowledge of AM, their ontogeny and development during health and disease, and how dysregulated AM lipids play a key role in disease processes, from initiation to resolution.

While lipid-laden macrophages are observed across a broad spectrum of lung diseases, their occurrence has largely been considered consequential. Recent advances in lipidomic profiling of single cell types has revealed that disturbances to lipid homeostasis occur early in disease in tissue-resident cells. Comparisons between inflammatory and fibrotic injury models reveal specific alveolar macrophage subsets with different lipid utilization that contribute to the disease process.

Understanding the intricate web of AM population seeding and development and how this niche is perturbed by lipid disturbances may help provide leverage for new interventions.