Introduction:
Alveolar macrophages serve as vital immune cells for responding to inhaled foreign substances through innate and adaptive immune mechanisms. They inhabit the airways and lung tissues from early life or are derived from blood monocytes. Like macrophages in other body regions, alveolar macrophages exhibit natural flexibility, adapting to their phenotype and function based on their surrounding environment. Changes in alveolar macrophage phenotype have been linked to chronic inflammatory conditions and disease progression in various lung diseases, including chronic obstructive pulmonary disease (COPD).
Alveolar macrophages possess diverse functional capabilities, including phagocytosis of inorganic and organic particles like viruses, bacteria, and fungi, processing of engulfed material, and production of signaling molecules. Acting as caretakers of the airways, they also aid in removing dead and dying cells and cellular debris.
What Are Alveolar Macrophages?
Alveolar macrophages are the first population of mononuclear phagocytes (MNPs) described, owing to their accessibility through bronchoalveolar lavage and their abundance, constituting up to 95 percent of lavaged cells in healthy individuals. They are crucial in clearing surfactants and foreign materials, ensuring lung cleanliness. Impaired alveolar macrophage function can lead to pulmonary alveolar proteinosis, a rare disorder treatable with granulocyte or macrophage colony-stimulating factor.
Despite initial studies relying on morphology and single markers for identification, flow cytometry now allows for more precise identification of human alveolar macrophages based on their size, granularity, and expression of markers like CD206, CD163, and CD169. Compared to other lung phagocytes, alveolar macrophages exhibit superior internalization of bacterial particles but do not upregulate certain activation markers upon exposure to bacteria.
Instead, they promote tolerance by suppressing lymphocyte activation and producing transforming growth factors and prostaglandins. Although typically quiescent, alveolar macrophages can mount inflammatory responses when necessary, releasing mediators like interleukin-8 to recruit neutrophils into the airways. Transcriptomic profiling has revealed their ability to fine-tune early cytokine responses upon stimulation.
What Is the Function of the Alveolar Macrophage in the Lungs?
The functions of alveolar macrophages are as follows:
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Alveolar macrophages are crucial for regulating innate immune responses in the lungs, defending against inhaled foreign substances like irritants, pollutants, bacteria, and viruses to maintain airway cleanliness.
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After engulfing foreign materials through phagocytosis, alveolar macrophages process them and act as antigen-presenting cells, initiating the adaptive immune response.
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These innate and adaptive immune responses are mutually dependent, with LMs playing a pivotal role in coordinating both.
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Post-processing of inhaled foreign matter, alveolar macrophages release mediators that stimulate the bone marrow, encouraging the release of monocytes and their recruitment into the lungs, where they differentiate into tissue and airway macrophages, complementing resident macrophages.
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Alveolar macrophage's responses to engulfed foreign matter may vary depending on particle characteristics like size, geometry, and surface properties.
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While alveolar macrophages efficiently phagocytose smaller particles, they often collaborate to form giant multinucleated cells to handle larger ones.
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Particle shape can also influence alveolar macrophage phagocytosis ease, with uneven or rough surfaces promoting cell adherence and affecting macrophage production of pro-inflammatory cytokines and chemokines.
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Organic foreign materials, like microorganisms, necessitate opsonization for Fc receptor-mediated phagocytosis and clearance or interaction with toll-like receptors recognizing both gram-positive and gram-negative bacteria for phagocytosis.
What Are the Consequences of Alveolar Macrophage Dysfunction?
In chronic inflammatory lung diseases like COPD, asthma, and cystic fibrosis, the normal balance is disrupted, leading to ongoing inflammation. Despite an increase in the number of macrophages, their function becomes dysregulated, contributing to an imbalance in the lung microbiome, which is recognized as a factor in diseases like COPD.
In the first indication of defective alveolar macrophage function in COPD, researchers observed a significant impairment in the phagocytosis of apoptotic airway epithelial cells by alveolar macrophages from COPD patients compared to those from non-smokers of similar age. Interestingly, there was no impairment when using polystyrene beads, suggesting differences in responses based on the phagocytosis trigger.
This impairment was attributed to either the failure to recognize apoptotic markers on epithelial cells or the satiety hypothesis, suggesting downregulation of subsequent phagocytosis due to previous clearance.
Previous studies have identified a fundamental phagocytic defect in alveolar macrophages from COPD patients when exposed to three clinical strains, which cannot be solely attributed to active smoking. However, macrophages derived from peripheral blood monocytes of COPD patients did not show phagocytic impairment, suggesting a localized immunologic defect.
Despite theories suggesting intracellular survival of bacteria in macrophages as a factor in intracellular bacterial viability, it was observed in COPD alveolar macrophages. Instead, the inability of alveolar macrophages in COPD to mount a phagocytic response may allow bacterial pathogens to evade immune clearance, perpetuating inflammation.
Each bacterial species causing infection in COPD patients exhibits unique colonization dynamics and immune interactions with human cells. Nontypeable Haemophilus influenza and Moraxella catarrhalis are the most prevalent bacteria associated with COPD exacerbations. Host responses to these bacteria, including lymphocyte and antibody responses, play significant roles in exacerbations. Streptococcus pneumonia, another mucosal pathogen, is a leading cause of community-acquired pneumonia in COPD. Each of these bacterial pathogens presents distinct immunologic triggers for different host pathways.
In response to noxious agents and epithelial damage, tissue-resident innate immune cells, particularly macrophages, initiate a robust immune response in the human lung. Alveolar macrophages, along with bronchial and interstitial macrophage populations, are key players in this response.
Despite their distinct localization within the lung, the functions of these macrophage populations, particularly interstitial macrophages, still need to be characterized due to limited access to normal human lung samples. Recent studies have identified four distinct mononuclear phagocytic cells resident in the human lung, highlighting the diversity of the myeloid population in health. However, changes in lung resident populations of mononuclear phagocytes and contributions from circulating macrophages may occur in chronic inflammatory states.
Conclusion:
The dysfunction of alveolar macrophages plays a significant role in various pulmonary disorders, including pulmonary alveolar prognosis and chronic inflammatory lung diseases like COPD. Despite their crucial role in maintaining lung homeostasis and defense against pathogens, impaired alveolar macrophage function can compromise the clearance of surfactants and foreign materials, exacerbating inflammation and contributing to disease progression. Understanding the mechanisms underlying alveolar macrophage dysfunction is vital for developing targeted therapeutic interventions to restore their normal function and mitigate the impact of pulmonary diseases on patient’s health and well-being.
