Alveolar Macrophage - Releasing The Brakes On Alveolar Macrophages

Releasing The Brakes On Alveolar Macrophages

Toll-like receptors (TLRs) are signaling PRRs, a family of receptors that is capable of recognizing conserved microbial patterns like components of the bacterial cell wall, microbial nucleic acids, and bacterial motility. 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. Upon detection of a dangerous antigen by interaction between TLR and PAMPs, TLR triggers inflammatory and defensive responses in the host by inducing actin polymerization in alveolar macrophages (a crucial component in endocytosis and motility). Actin polymerization in alveolar macrophages causes the suppression of integrin expression, which in turn causes the deactivation of TGF-β and the downregulation of the basal phosphorylation level of SMAD 2/3; subsequently leading to the activation and detachment from the alveolar epithelial cells of alveolar macrophages . Upon releasing the brakes of macrophage activation, macrophages become primed for phagocytosis and begin to secrete proinflammatory cytokines (TNF-α and IL-6).

The priming of macrophages involves the enhancement of respiratory burst activity by IFN- γ and TNF-α. IFN- γ induces both an increased affinity of the NADPH oxidase for NADPH in macrophages, as well as an increased rate of gene transcription and message expression for gp91phox protein. TNF-α acts as an autocrine stimulus by increasing the expression of both p47phox and p67phox transcripts. The ROIs produced during the respiration burst response, in turn, enhance production of TNF-α by macrophages.

Halting the Activated Alveolar Macrophage Gas exchange must be restored as quickly as possible to avoid collateral damage, so activated lymphocytes secrete IFN- γ to stimulate the production of matrix metalloproteinase MMP-9 by macrophages. AMs have been reported to produce MMP-9 partly via PGE2-dependent PKA signaling pathways, which are the pathways involved in the inhibition of phagocytosis. MMP-9 activates latent TGF-β, reinducing expression of αvβ6 on alveolar epithelial cells, thereby putting the brakes back on AMs. Activation of TGF-β is also advantageous because its production stimulates collagen synthesis in interstitial fibroblasts, which is necessary for restoring alveolar wall architecture.

Recent Research into Alveolar Macrophages and Future Prospects Research into AM functionality has been on the rise since AMs are one of the first lines of a defense against invasive pathogens. One of the most prominent fields is investigating liposomes as deliverers of antibiotics for treatment of respiratory intracellular infections. Intracellular parasites, such as M. tuberculosis, C. pneumoniae, L. monocytogenes, L. pneumophila, and F. tularensis, (to name a few) are taken up by AMs via phagocytosis, but are resistant to the biocidal mechanisms of AMs and can survive intracellularly, thus inducing severe respiratory infections. Pulmonary tuberculosis is caused by M. tuberculosis, and is now a major infectious disease worldwide and its incidence is increasing, especially in association with the AIDS pandemic. For sterilization of intracellular parasites in AMs, antibiotics are normally given orally or intravenously, but much of the antibiotics disperse to many different tissues, diminishing its effectiveness. Pulmonary administration of mannosylated liposomes is a much more direct, efficient route in targeting AMs; it enhances antimicrobial effect, reduces the dosage needed, and avoids unnecessary distribution to the blood. Since mannose receptors are exclusively expressed on the surface of AM, mannosylation of liposomes is an appealing approach to cell-selective targeting to AM. The efficacy of pulmonary administration of ciprofloxacin (CPFX) incorporated into mannosylated liposomes (mannosylated CPFX-lipososomes) was examined in rats, and determined to be an efficient means to target AMs.