Introduction
Macrophages constitute the most numerous immune cells in the lung environment when homeostasis (steady state of internal, physical, and chemical conditions of the body) is present, making them the best candidates to direct the innate defense of the airways. The diversity of lung macrophages allows for significant specialization, appropriate responses to environmental signals, and quick phenotypic and physiological changes in response to a wide range of cytokines and microbial signals.
What Are Macrophages?
Macrophages are found in almost all body tissues and are an essential part of the primary innate immune response. They are the most prevalent immune cell type in the lung when homeostasis is present. A diverse population of immune cells known as pulmonary macrophages performs a number of specialized tasks, including the maintenance of pulmonary homeostasis, microbial clearance, removal of cellular debris, immune surveillance, responses to infections, and the resolution of inflammation. Tissue residency, variations in origin, and environmental influences are the root causes of this extraordinary plasticity.
What Is the Biology of Alveolar Macrophages?
Alveolar macrophages (AMs) and interstitial macrophages (IMs) are two of at least two distinct macrophage populations found in the lung at homeostasis. Each is distinguished by its particular setting, attributes, and functions. The expression patterns of the integrins CD11b and CD11c can be used to distinguish between populations of 3 AM and IM. The 3 AMs, which are found in the airway lumen, are distinguished from macrophages found in other tissue compartments by having high CD11c expression but low CD11b expression. In contrast, IMs express increased levels of CD11b and low levels of CD11c and are found in the lung parenchyma. IMs are believed to have a regulatory role within the lung tissue, while AMs play a crucial role in preserving immunological host defense and homeostasis in the lung. While AMs influence regulation through non-specific lines of defense such as high phagocytic ability, antimicrobial secretion, nitric oxide (NO), tumor necrosis factor (TNF), and interferon (IFN), it has been hypothesized that IMs have a higher propensity to release interleukin (IL-10) and other specific cytokines linked to the adaptive immune response.
According to their level of activation, macrophages have been broadly categorized as M1 and M2, similar to the T helper cell Th1/Th2 paradigm. In response to IFN (interferon), lipopolysaccharide, and TNF, M1 macrophages (also known as classically activated macrophages) produce proinflammatory cytokines, direct the destruction of intracellular pathogens, and support a local Th1 environment. Alternatively, activated macrophages also referred to as M2 macrophages, have a more varied phenotype and are distinguished by their involvement in type 2 immune responses. There are three subsets of M2 macrophages: M2a, M2b, and M2c. These subsets support tissue remodeling and matrix deposition (M2b), immune regulation (M2a), and parasite encapsulation and destruction (M2a) (M2c).
The development of tumors has also been linked to M2 macrophages. The transition to an M1 or M2 phenotype has been connected with particular transcriptional control, similar to Th1/Th2 lymphocyte polarization. In studies on humans and mice, it has been demonstrated that the transcription factor IFN regulatory factor 5 regulates the M1 phenotype and directs the production of proinflammatory cytokines by these cells. Due to their high plasticity, macrophages can adjust their activity and develop mixed phenotypes in pulmonary inflammatory disease according to the local microenvironment. It is clear that the macrophage phenotype is adapted to the specific immunological requirement during disease rather than surviving at the extreme ends of the M1 or M2 spectrum. Importantly, data defining the M1 or M2 paradigm are largely based on in vitro studies using isolated peripheral blood monocytes, and caution should be used during disease progression and within the patient's airways when extrapolating phenotypical activity from these cell culture studies to activation status.
How Macrophage Mediates Airway Disease?
A significant complication of long-term, inflammatory pulmonary diseases is respiratory tract infections (RTIs), which have a wide range of potential causes. Molecular patterns associated with pathogens that are expressed by microbes and pattern recognition receptors that are expressed by macrophages may interact to cause a variety of reactions to a respiratory infection. Rhinovirus, influenza, respiratory syncytial virus, Mycobacterium tuberculosis, and Streptococcus pneumonia all appear to be primarily mediated by macrophages.
What Is the Role of Macrophages in Aging?
When compared to younger populations, the elderly have a higher incidence of infectious disease-related morbidity, particularly when it comes to RSV (respiratory syncytial virus), viral influenza, and pneumococcal pneumonia. This is because as people age, their immune systems become less able to fight off infections and mount protective immune responses. Inflammaging refers to an improved homoeostatic activation of the innate immune system in the elderly in the absence of an immunological stimulus. This phenomenon is characterized by increased levels of tissue and circulating proinflammatory cytokines like IL-1, IL-6, and TNF. Although it is diminished with advancing age, autophagy is essential for maintaining macrophage homeostasis and function. In contrast to the reduced phagocytosis and nitrite burst activity, this causes a markedly increased inflammatory cytokine response in macrophages. Consequently, it has been proposed that controlling autophagy may maintain macrophage function as one age and lower the morbidity and mortality linked to inflammation-related aging.
Conclusion
It is clear that macrophages are crucial in directing the immune response to the environment that is inhaled and manipulating them offers an intriguing therapeutic approach. Importantly, it is known that there are at least two populations of pulmonary macrophages, IMs in the tissue and AMs in the airways compartment. Each population represents a distinct lineage with particular origins, phenotypes, and functions deserving of study and therapeutic exploitation, even though each population likely shares a variety of functions and roles with the other. In fact, a recent study in a model of hereditary pulmonary alveolar proteinosis showed that transplanting pulmonary macrophages into mice was both safe and well tolerated. Numerous lines of research indicate that it may be more important to understand how these cells behave in situ during chronic pulmonary diseases rather than concentrating on the M1 or M2 paradigm and studying in vitro differentiated monocytes. The challenge is to use the knowledge gained from mechanistic studies of macrophages to develop targeted therapies for pulmonary disease treatment. Macrophages play a wide variety of roles and exhibit a plastic nature.
