Alveolar macrophage
For example, phagocytosis of IgG-opsonized pathogens occurs through the Fcγ receptors (FcγR), and involves phagocyte extensions around the microbe, resulting in the production of pro-inflammatory mediators.
Conversely, complement receptor-mediated pathogen ingestion occurs without observable membrane extensions (particles just sink into the cell) and does not generally results in an inflammatory mediator response.
Following internalization, the microbe is enclosed in a vesicular phagosome which then undergoes fusion with primary or secondary lysosomes, forming a phagolysosome.
[9] The enzyme responsible for the elicitation of the respiratory burst is known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is composed of five subunits.
[9] 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.
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.
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.
To prevent uncontrolled inflammation in the lower respiratory tract, alveolar macrophages secrete nitric oxide, prostaglandins, interleukin-4 and -10(IL-4, IL-10), and transforming growth factor-β (TGF-β).
[14] There are two explanations for the lack of responsiveness in the promoter of human inducible nitric oxide synthetase (iNOS) to NO activation by lipopolysaccharides (LPS) + interferon gamma (IFNγ).
[14] 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.
[14] 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.
[11][16] EP2 and EP4 receptors signal primarily through stimulatory G protein (Gs), increasing adenylyl cyclase (AC) activity and subsequent cAMP formation.
[11] The killing of phagocytosed bacteria by AMs is dependent upon several distinct microbicidal mechanisms, like the reduced NADPH oxidase-mediated release of ROI.
[17][18] Ig is a class of antibody found only in mammals that plays an important role in allergy response and defense against many kinds of pathogens by protecting the body against them by complement activation, opsonization for phagocytosis, and neutralization of their toxins.
As an inhibitory cytokine, IL-10 facilitates the infection of human alveolar macrophages and monocytes by completely reversing the protective effect of IFNγ against intracellular Legionella pneumophila replication.
[20][21] TGF-β is a multifunctional cytokine that modulates a variety of biological processes such as cell growth, apoptosis, extracellular matrix synthesis, inflammation, and immune responses.
[24] Normally mature TGFβ is secreted as a latent complex with its N-terminal fragment, latency-associated peptide (LAP), which inhibits its activity.
[22] Binding of activated TGF-β to its receptors expressed on alveolar macrophages induces a downstream signaling cascade, including phosphorylation of receptor-regulated Small Mothers Against Decapentaplegic (R-SMAD)homologs 2 and 3.
Once in the nucleus, these complexes accumulate and eventually act as a transcription factors, regulating the expression of TGF-β target genes.
[10] Although bacteria have evolved means of evading host defense mechanisms, they express PAMPs, such as lipoglycans and lipoproteins that are recognized by cells of the innate immune system through the TLRs.
[10] Upon binding of PAMPs to TLRs, the TLR triggers inflammatory and defensive responses in the host cell, inducing actin polymerization in alveolar macrophages (a crucial component in endocytosis and motility).
[9] Gas exchange must be restored as quickly as possible to avoid collateral damage, so activated lymphocytes secrete IFNγ to stimulate the production of matrix metalloproteinase MMP-9 by macrophages.
[7][22][26] Activation of TGF-β is also advantageous because its production stimulates collagen synthesis in interstitial fibroblasts, which is necessary for restoring alveolar wall architecture.
