**3. Physiological roles of alveolar macrophage phagocytosis in acute LRTIs**

## **3.1 Development and maintenance of alveolar macrophages**

Lung-resident alveolar macrophages play a leading role in the clearance of airborne microorganisms that enter the alveoli during inspiration. Murine alveolar macrophages originate from fetal monocytes [34]. The development of alveolar macrophages from fetal monocytes is regulated by granulocyte-macrophage colonystimulating factor (GM-CSF) and the downstream transcription factor peroxisome proliferator-activated receptor γ (PPARγ) [35]. After birth, however, alveolar macrophages are essentially not replenished by bone marrow-derived monocytes but are self-maintained by the paracrine action of GM-CSF secreted by epithelial cells [35]. Moreover, further maturation of alveolar macrophages requires transforming growth factor (TGF)-β1, which is secreted in an autocrine manner and upregulates PPARγ expression [36]. A similar developmental pathway is presumed to occur in humans since immunostaining of lung sections from stillborn infants revealed that interstitial macrophages were abundant in the interstitium, whereas mature alveolar macrophages were completely absent in the alveoli [37]. The acquisition of specific functions by alveolar macrophages, including advanced phagocytic capacity, is partly due to the unique maturation processes in the alveolar microenvironment, where GM-CSF acts as a key regulator.

#### **3.2 Phagocytic receptors expressed on alveolar macrophages**

### *3.2.1 Scavenger receptors and their functions*

Among the PRRs, two members of the scavenger receptor superfamily proteins, macrophage scavenger receptor 1 (MSR1) and macrophage receptor with collagenous

#### *Physiological Role of Alveolar Macrophage in Acute Lower Respiratory Tract Infection… DOI: http://dx.doi.org/10.5772/intechopen.110509*

structure (MARCO), recognize both Gram-positive and Gram-negative bacteria by detecting their pyrogenic cell wall components, lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively [38–40]. Alveolar macrophages constitutively express MSR1 and MARCO, which are essential to eliminate airborne pathogenic bacteria. Knockout mice lacking MSR1 or MARCO displayed an impaired ability to remove live bacteria, exacerbated pneumonia, and reduced survival after intranasal inoculation with *S. pneumoniae* [41, 42]. The expression and function of MSR1 and MARCO are conserved in human alveolar macrophages [43]. Further, mice lacking another scavenger receptor, CD36, exhibited similar phenotypes during pulmonary infection caused by the Gram-positive bacterium *Staphylococcus aureus* [44]. In addition, alveolar macrophages are characterized by higher expression of scavenger receptors with one or more C-type lectin-like domains, such as β-1,3/1,6-d-glucan receptor dectin-1 [45, 46] and the mannose receptor CD206 [37, 47], which pivotally contribute to the removal of fungi and bacteria from the alveoli by detecting their respective target carbohydrates that cover the cell wall surface.

### *3.2.2 Opsonin receptors and their functions*

Murine alveolar macrophages highly express Fcγ receptors FcγRI/II/III and further enhance their phagocytic activity when Gram-negative bacteria, *Pseudomonas aeruginosa*, are opsonized with IgG, whereas they hardly express complement receptors CR1/2/3, and their ability is not affected by complement opsonization [48]. Further, the other subset of complement receptor CRIg is expressed in murine and human alveolar macrophages [49], but its ability to directly recognize Gram-positive bacteria by detecting LTA suggests that it can act as a PRR in the lungs [50]. Notably, alveolar macrophages isolated from GM-CSF-knockout mice were deficient in Fcγ receptors and had impaired phagocytic activity against both IgG-opsonized and non-opsonized latex beads and their phenotypes were restored by epithelial cell-specific expression of GM-CSF [51]. A recent study reported that human alveolar macrophages express FcγRI/II/III at higher levels than other systemic counterparts, such as macrophages in the bone marrow, spleen, and liver [52]. Moreover, peripheral blood monocytederived macrophages that differentiated in GM-CSF-containing culture exhibited properties that were partially similar to those of alveolar macrophages, expressing a larger amount of FcγRI/II compared with that of their counterparts [52].
