Alveolar macrophages reside in the airspaces juxtaposed with epithelial cells and function as critical regulators of pulmonary host defenses against bacterial, viral, and fungal infection. Under physiological condition, alveolar macrophages remain in a quiescent state, produce low levels of cytokines, exhibit poor phagocytic activity and suppress the induction of the adaptive immunity and humoral immunity. Nevertheless, upon interaction with noxious particles, alveolar macrophages can quickly produce a broad spectrum of cytokines and display high phagocytic activity to clear pathogens, apoptotic and cellular debris in the lung.
Like other tissue resident macrophages, alveolar macrophages display distinct and even sometime opposite abilities to initiate immune responses or to promote the resolution of lung inflammation. Whether alveolar macrophages serve as a cellular inflammation trigger or a terminator of lung inflammatory injury primarily depends on their differentiation, phenotype, function, and cell-cell interactions which are regulated by their unique microenvironment of the lung via modifing gene expression profiles. In response to different signals, macrophages may differentiate into pro-inflammatory M1 (also named classically activated macrophages) or anti-inflammatory M2 phenotype (also named alternatively activated macrophages). Following a variety of infectious and noninfectious noxious stimuli, alveolar macrophages sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NODs), and intracellular helicases like retinoic acid inducible gene I (RIG-I). Upon activation alveolar macrophages initiate inflammatory responses in the lung and recruit activated neutrophils and macrophages into the site of infection by mean of the release pro-inflammatory cytokines such as type I IFN, TNF-a, interleukin (IL-6) and IL-1ß. As the pathogen is cleared and pro-inflammatory signaling events decline, neutrophils undergo apoptosis. Phagocytosis of apoptotic neutrophils (efferocytosis) by alveolar macrophages accelerates the resolution of lung inflammation via suppressing secretion of proinflammatory cytokines and facilitating production of anti-inflammatory cytokines, such as transforming growth factor-ß and IL-10.
By virtue of their versatile functions, alveolar macrophages represent an attractive target for intervention at various stages of acute lung injury/ARDS. However, our knowledge is far from complete with regard to macrophage biology in lung inflammation and its resolution, especially in human. Elucidation of molecular mechanisms and determinants of alveolar macrophage plasticity and polarized activation during different phases of lung inflammation will provide new insights into the development of macrophage-targeted diagnostic and therapeutic strategies. It remains to understand how microenvironmental signals regulate the homeostatic renewal of alveolar macrophages during the pathogenesis and resolution of lung inflammation. In addition, a comprehensive understanding of the mechanisms and role of efferocytosis by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions in lung inflammation may lead to the development of novel therapeutic modalities in treating acute lung injury/ARDS.
Alveolar macrophages reside in the airspaces juxtaposed with epithelial cells and function as critical regulators of pulmonary host defenses against bacterial, viral, and fungal infection. Under physiological condition, alveolar macrophages remain in a quiescent state, produce low levels of cytokines, exhibit poor phagocytic activity and suppress the induction of the adaptive immunity and humoral immunity. Nevertheless, upon interaction with noxious particles, alveolar macrophages can quickly produce a broad spectrum of cytokines and display high phagocytic activity to clear pathogens, apoptotic and cellular debris in the lung.
Like other tissue resident macrophages, alveolar macrophages display distinct and even sometime opposite abilities to initiate immune responses or to promote the resolution of lung inflammation. Whether alveolar macrophages serve as a cellular inflammation trigger or a terminator of lung inflammatory injury primarily depends on their differentiation, phenotype, function, and cell-cell interactions which are regulated by their unique microenvironment of the lung via modifing gene expression profiles. In response to different signals, macrophages may differentiate into pro-inflammatory M1 (also named classically activated macrophages) or anti-inflammatory M2 phenotype (also named alternatively activated macrophages). Following a variety of infectious and noninfectious noxious stimuli, alveolar macrophages sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NODs), and intracellular helicases like retinoic acid inducible gene I (RIG-I). Upon activation alveolar macrophages initiate inflammatory responses in the lung and recruit activated neutrophils and macrophages into the site of infection by mean of the release pro-inflammatory cytokines such as type I IFN, TNF-a, interleukin (IL-6) and IL-1ß. As the pathogen is cleared and pro-inflammatory signaling events decline, neutrophils undergo apoptosis. Phagocytosis of apoptotic neutrophils (efferocytosis) by alveolar macrophages accelerates the resolution of lung inflammation via suppressing secretion of proinflammatory cytokines and facilitating production of anti-inflammatory cytokines, such as transforming growth factor-ß and IL-10.
By virtue of their versatile functions, alveolar macrophages represent an attractive target for intervention at various stages of acute lung injury/ARDS. However, our knowledge is far from complete with regard to macrophage biology in lung inflammation and its resolution, especially in human. Elucidation of molecular mechanisms and determinants of alveolar macrophage plasticity and polarized activation during different phases of lung inflammation will provide new insights into the development of macrophage-targeted diagnostic and therapeutic strategies. It remains to understand how microenvironmental signals regulate the homeostatic renewal of alveolar macrophages during the pathogenesis and resolution of lung inflammation. In addition, a comprehensive understanding of the mechanisms and role of efferocytosis by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions in lung inflammation may lead to the development of novel therapeutic modalities in treating acute lung injury/ARDS.
