Alveolar macrophages: guardians of the alveolar lipid galaxy

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Keywords: alveolar macrophage; cholesterol; lipid; lung disease.

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FIGURE 1

Lipids and cells in the alveolar space. (i) Surfactant is synthesized in alveolar type II pneumocytes (AT2 cells) and stored in lamellar bodies (LB). LB are secreted into the alveolar space and form a lipid monolayer film that allows for the surface tension-reducing properties of surfactant and efficient gas exchange. The ratio of lipids, particularly the amount of cholesterol, is absolutely essential for maintaining these biophysical properties. (ii) The key partner to AT2 cells are alveolar macrophages (AM), which are responsible for degrading surfactant phospholipid that can be stored or effluxed (via the ABC transporters ABCA1 and ABCG1) along with free cholesterol for transport back to the liver. (iii) AM arise during embryogenesis from fetal precursors that seed developing lung tissue and differentiate into primitive macrophages. (iv) Full development of resident alveolar macrophages (RAM) occurs after birth following translocation of prealveolar macrophages (p-macrophages) into the alveolar space. The core developmental process or p-macrophages into RAM is driven by GM-CSF, produced by AT2 cells. (v) GM-CSF drives expression of key transcription factors PU.1, C/EBPα, PPARγ, and LXRα/β, to shape and preserve RAM programming in the alveolar niche.

FIGURE 2

Lipid dysregulation during injury and disease. (i) There are significant changes that occur in lipid composition and metabolism during disease and lung injury. An injury can be genetic (loss of GM-CSF signaling, as seen in pulmonary alveolar proteinosis (PAP), or acid sphingomyelinase (ASM) deficiency), chemical/environmental (cigarette smoke exposure (CSE), sarcoidosis), or due to a disease process (chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, or lung cancer). (ii) Lipid-laden, foamy resident alveolar macrophages (RAM) are present in a wide-range of lung diseases including PAP, COPD, pulmonary fibrosis, and lung cancer; arising due to changes in RAM lipid handling ability. Modulating lipid metabolism and cholesterol efflux pathways (via PPARγ agonists and statins) has shown promise in decreasing foamy RAM and improving disease. (iii) Dysregulated RAM lipid homeostasis and lung injury induces recruitment of monocyte-derived macrophages (recAM) to the alveolar space. These recAM have a different transcriptional profile, fuel requirements, and lipid handling capabilities from healthy RAM, and ultimately become lipid-laden foamy recAM. (iv) Foamy RAM and recAM are functionally altered, pro-inflammatory, and pro-fibrotic and (v) Promote the transition from fibroblasts to myofibroblasts, thus exacerbating disease progression.