Alveolar macrophage
An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.
Activity of the alveolar macrophage is relatively high, because they are located at one of the major boundaries between the body and the outside world. They are responsible for removing particles such as dust or microorganisms from the respiratory surfaces.
Alveolar macrophages are frequently seen to contain granules of exogenous material such as particulate carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers.
The alveolar macrophage is the third cell type in the alveolus; the others are the type I and type II pneumocytes.
Comparison of pigmented pulmonary macrophages
Function
Alveolar macrophages are phagocytes that play a critical role in homeostasis, host defense, and tissue remodeling. Their population density is decisive for these many processes. They are highly adaptive and can release many secretions, to interact with other cells and molecules using several surface receptors. Alveolar macrophages are also involved in the phagocytosis of apoptotic and necrotic cells. They need to be selective of the material that is phagocytized to safeguard the normal cells and structures. To combat infection, the phagocytes facilitate many pattern recognition receptors to help recognize pathogen-associated molecular patterns on the surface of pathogenic microorganisms. PAMPs all have the common features of being unique to a group of pathogens but invariant in their basic structure; and are essential for pathogenicity. Proteins involved in microbial pattern recognition include mannose receptor, complement receptors, DC-SIGN, Toll-like receptors, the scavenger receptor, CD14, and Mac-1. PRRs can be divided into three classes:- signaling PRRs that activate gene transcriptional mechanisms that lead to cellular activation,
- endocytic PRRs that function in pathogen binding and phagocytosis, and
- secreted PRRs that usually function as opsonins or activators of complement.
Following internalization, the microbe is enclosed in a vesicular phagosome which then undergoes fusion with primary or secondary lysosomes, forming a phagolysosome. There are various mechanisms that lead to intracellular killing; there are oxidative processes, and others independent of the oxidative metabolism. The former involves the activation of membrane enzyme systems that lead to a stimulation of oxygen uptake, and its reduction to reactive oxygen intermediates, molecular species that are highly toxic for microorganisms. The enzyme responsible for the elicitation of the respiratory burst is known as nicotinamide adenine dinucleotide phosphate oxidase, which is composed of five subunits. One component is a membrane cytochrome made up of two protein subunits, gp91phox and p22phox; the remaining three components are cytosolic-derived proteins: p40phox, p47phox, and p67phox. NADPH oxidase exists in the cytosol of the AM when in a quiescent state; but upon activation, two of its cytosolic components, p47phox and p67phox, have their tyrosine and serine residues phosphorylated, which are then able to mediate translocation of NADPHox to the cytochrome component, gp91phox/p22phox, on the plasma membrane via cytoskeletal elements.
Compared to other phagocytes, the respiratory burst in AM is of a greater magnitude. Oxygen-independent microbicidal mechanisms are based on the production of acid, on the secretion of lysozymes, on iron-binding proteins, and on the synthesis of toxic cationic polypeptides. Macrophages possess a repertoire of antimicrobial molecules packaged within their granules and lysosomes. These organelles contain a myriad of degradative enzymes and antimicrobial peptides that are released into the phagolysosome, such as proteases, nucleases, phosphatases, esterases, lipases, and highly basic peptides. Moreover, macrophages possess a number of nutrient deprivation mechanisms that are used to starve phagocytosed pathogens of essential micronutrients. Certain microorganisms have evolved countermeasures which enable them to evade being destroyed by phagocytes. Although lysosomal-mediated degradation is an efficient means by which to neutralize an infection and prevent colonization, several pathogens parasitize macrophages, exploiting them as a host cell for growth, maintenance and replication. Parasites like Toxoplasma gondii and mycobacteria are able to prevent fusion of phagosomes with lysosomes, thus escaping the harmful action of lysosomal hydrolases. Others avoid lysosomes by leaving the phagocytic vacuole, to reach the cytosolic matrix where their development is unhindered. In these instances, macrophages may be triggered to actively destroy phagocytosed microorganisms by producing a number of highly toxic molecules and inducing deprivational mechanism to starve it. Finally, some microbes have enzymes to detoxify oxygen metabolites formed during the respiratory burst.
When insufficient to ward off the threat, alveolar macrophages can release proinflammatory cytokines and chemokines to call forth a highly developed network of defensive phagocytic cells responsible for the adaptive immune response. During COVID-19 infection, alveolar macrophages play a dual role by acting as the first line of defense against SARS-CoV-2 in the alveolar space, while also contributing to the hyperinflammatory response through excessive cytokine production, which can exacerbate lung damage and acute respiratory distress syndrome.
The lungs are especially sensitive and prone to damage, thus to avoid collateral damage to type I and type II pneumocytes, alveolar macrophages are kept in a quiescent state, producing little inflammatory cytokines and displaying little phagocytic activity, as evidenced by downregulated expression of the phagocytic receptor Macrophage 1 antigen. AMs actively suppress the induction of two of the immunity systems of the body: the adaptive immunity and humoral immunity. The adaptive immunity is suppressed through AM's effects on interstitial dendritic cells, B-cells and T-cells, as these cells are less selective of what they destroy, and often cause unnecessary damage to normal cells. To prevent uncontrolled inflammation in the lower respiratory tract, alveolar macrophages secrete nitric oxide, prostaglandins, interleukin-4 and -10, and transforming growth factor-β.
Role of signaling molecules
Nitric oxide
is a major source of immunomodulation in rodents, and is produced by enzyme nitric oxide synthetase type 2 in the alveolar macrophage. NO inhibits tyrosine phosphorylation of the kinases involved in production of the interleukin-2 receptor, the expression of which is fundamental for T cell proliferation. In humans, however, NOS2 activity has been difficult to verify.There are two explanations for the lack of responsiveness in the promoter of human inducible nitric oxide synthetase to NO activation by lipopolysaccharides + interferon gamma. The first is that there are various inactivating nucleotide variations in the human counterpart of the enhancer element that regulates LPS/IFNγ induced expression of the mouse NOS2 gene. The second is because of the absence of a nuclear factor in human macrophages that is required for optimum expression of gene NOS2. It is assumed that the difficulty in verifying NOS2 is due to a much more tightly controlled expression in human AMs as compared to that in the rodent AMs. NOS2 is part of an autoregulatory feedback loop, wherein an allergen or provoker stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production. In rats, NO inhibits the granulocyte-macrophage colony-stimulating factor -mediated maturation of dendritic cells, and in humans it inhibits the TNF-alpha-mediated maturation of human dendritic cells, through cyclic GMP-dependent mechanisms. NO prolongs the ability of human dendritic cells to internalize antigens at sites of inflammation, therefore modulating the beginning steps leading to antigen-specific immune responses.
NO production has been implicated as relevant to the pathology of asthma. People with asthma show an increased expression of iNOS in airway epithelial cells and an increased level of nitric oxide in exhaled air.