Macrophages and macrophage-like cells are present in all mammalian organs with substantial heterogeneity and phenotypic specialization that is regulated in tissue-specific manner. In the lung, there are two distinct macrophage populations: alveolar macrophages, which are in close contact with the type I and II epithelial cells of alveoli (1); and interstitial macrophages, which reside in the parenchyma between the microvascular endothelium and alveolar epithelium (2). Alveolar macrophages derive from yoke sac procurers of fetal monocytes, which populate the alveoli shortly after birth and persist over the lifespan via self-renewing embryo-derived populations independently of bone marrow contribution (3–5). Following inflammatory insults, bone marrow-derived monocytes are recruited to the lung and differentiate into alveolar macrophages (6–8). Terminal differentiation and maturation of lung macrophages is dependent on granulocyte macrophage-colony stimulating factor and transduced by the transcription factors, Pu. 1 (9). The functional phenotype of alveolar macrophages is modulated by the unique microenvironment of the lung that includes intimate contact with epithelial cells, high oxygen tension, and exposure to surfactant-rich fluid. Alveolar macrophages are critical for tissue homeostasis, host defense, clearance of surfactant and cell debris, pathogen recognition, initiation and resolution of lung inflammation, and repair of damaged tissue (10). Under physiological conditions, alveolar macrophages produce low levels of inflammatory cytokines, maintain high phagocytic activity, and generally suppress inflammation and adaptive immunity (1).

Alveolar macrophages are the first line of defense against pollutants and pathogenic microbes that initiate an innate immune response in the lung. Two phenotypes of alveolar macrophages have been identified: classically activated macrophage (M1 macrophage) and alternatively activated macrophage (M2 macrophage). M1 macrophages respond to microbial factors and Th1 proinflammatory cytokines to exhibit glycolytic metabolism that is associated with inflammatory cytokine release, enhanced bacterial killing, and the recruitment of immune cells into the lung parenchyma and alveolus. In comparison, M2 macrophages are induced by exposure to the Th2 cytokines to undergo oxidative metabolism that is associated with anti-inflammatory cytokine release, phagocytosis of apoptotic cells (efferocytosis) and collagen deposition that contribute to the resolution of inflammation and repair of damaged tissues (11, 12). The protean role of alveolar macrophage in the pathogenesis and resolution of lung inflammation is dependent on their ontogeny and the microenvironment associated with various noxious stimuli (13). Due to their remarkable plasticity, alveolar macrophages are highly specialized in reacting to environmental signals leading to rapid and reversible changes in their inflammatory phenotype (14). In response to damage-associated molecular patterns, pathogen-associated molecular patterns, cytokines, growth factors, and other mediators released in the microenvironment, alveolar macrophages are phenotypically and functionally modified to adopt pro-inflammatory, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-asthmatic, pro-resolving, or tissue regenerating properties (15, 16). The transcriptome and epigenetic landscape of alveolar macrophages are determined by the lung microenvironment (17). During lung inflammation, macrophages also constantly communicate with and epithelial cells, microvascular endothelial cells, neutrophils, macrophages, lymphocytes, fibroblasts, and stem or tissue …