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Alveolar macrophages (AMs) are resident macrophages of the airways and lungs, serving as the respiratory tract's primary immune sentinels. They are positioned in the lumens of airway spaces in close contact with lung epithelium and are involved in cellular debris clearance and pathological situations of pathogen invasion or tissue damage (lung fibrosis). An important difference in alveolar macrophages that distinguishes them from other macrophages is their expression of CD11c and Siglec F, both of which are not typically expressed in other macrophages.

Origin
It was thought that tissue-resident macrophages originated from circulating macrophages that infiltrated the tissue and were able to maintain the pool of cells. However, this was recently refuted because the amount of AM in circulating macrophage knock-out mice wasn't proven to be significantly different from the control mice. This suggests that a different cell population is at the origin of AMs development. It was shown that AMs could more likely have embryonic origins developing during embryogenesis from fetal macrophage populations in the embryonic yolk sac and the fetal liver. The AM precursors are highly likely to be derived from fetal liver monocytes that migrate to colonize the lungs. However, this doesn’t cancel out the contribution of the circulating macrophages and embryonic yolk sac monocytes to the AM pool. Actually, circulating monocytes have been seen to replenish the AM pool in the case of γ-herpesvirus infection or lung fibrosis. Under inflammatory conditions, circulating macrophages serve as precursors for AMs.

Development
The development of AM has been shown to be regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) secreted by lung epithelial cells during embryogenesis with levels peaking at birth. The increase in GM-CSF increases the expression of the master transcription factor regulating AM development, peroxisome proliferator-activated receptor gamma (PPAR-γ). GM-CSF binds to its receptor (GM-CSFR) allowing for the phosphorylation of the beta subunit of GM-CSFR. This initiates the downstream JAK2/STAT5 signaling pathway for PPAR-γ transcription. The GM-CSF-PPAR-γ pathway plays an active role in the developmental process of AM.

Additionally, TGFb produced by FL monocytes leads to their differentiation into AMs through autocrine and paracrine processes regulating PPAR-γ expression and transcriptional activity.

Immunological function of resident alveolar macrophages
In the homeostatic environment, AMs play an immunosuppressive role. TGFb and interleukin 10 (IL10) production from lung epithelial cells bind to their receptors on AMs (TGFbR and IL10R respectively) to mediate phagocytosis of dead cells and promote Treg cell generation via secretion of TGFb and expression of retinal dehydrogenases 1/2 (RALDH1/2). In an immunological environment, the resident AMs are able to exert a pro-inflammatory role. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) present on the resident AMs and they are able to recognize pathogen-associated molecular patterns (PAMPs) from microbes that make their way into the tissue. When the PAMPs (ligand) bind TLR 2, 4, and 9 on the AMs, the TLRs trigger a pro-inflammatory response by inhibiting the IL10 signaling pathway and activating the IL1, p38, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) downstream signaling cascade. Neutrophil extracellular traps can also trigger the pro-inflammatory role of resident alveolar macrophages in the case of acute lung injury models. The pro-inflammatory resident AMs secretes pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1, chemokines, antimicrobial peptides, oxygen metabolites, and proteases. These AMs also have greater phagocytic activity in the pro-inflammatory state.

Aspergillus fumigatus infection
The lungs are exposed to the exterior environment, there is a great possibility of inhaling microbes present in the air that can make their way into the alveolus. This is the case with fungal infections such as Aspergillus fumigatus which can cause invasive aspergillosis. AMs play a role in the clearance of such microbes. A. fumigatus conidia enters the lungs via inhalation where it meets the resident AMs that can trap this fungus using pseudopods or endocytosis. These resident alveolar macrophages can also kill the internalized microbe by endosome-phagosome fusion. They can also control conidia infection through NADPH oxidase and reactive oxygen species. If the primary attempts at clearance aren't successful, the AMs take up the sentinel role of producing cytokines and chemokines to recruit monocytes, neutrophils.

Chronic Obstructive Pulmonary Disease (COPD)
COPD is a progressive and irreversible inflammatory disease of the lower respiratory tract characterized by airflow obstruction, chronic bronchitis, and damage to the alveolar sacs. During COPD, AMs are associated with an activated phenotype marked by the secretion of matrix metalloproteases (MMPs) and impaired phagocytic function. This demonstrates how AMs can contribute to disease progression.

Alveolar Macrophage-targeted therapy
COVID-19, caused by infection with SARS-CoV-2, was first identified in late 2019 and quickly spread globally leading to a worldwide pandemic. AMs can be directly infected with SARS-CoV-2 and exhibit dysfunctional immune responses during COVID-19 diseases by slowing down the early innate response and accelerating a hyperinflammatory response at the late stage of the disease Therapeutic strategies have been developed to module AM activity during COVID-19 disease by promoting or blocking GS-CSF signaling. Promoting GM-CSF can help in AM maturation and improve airway clearance. This is particularly useful in cases of pneumonia-associated ARDS (Acute respiratory distress syndrome). GM-CSF inhibition on the other hand has proven to be helpful in patients suffering from hyperinflammation. This therapeutic approach has been shown to be effective in reducing the severity of late-stage of COVID-19 pneumonia.