**1. Introduction**

Lung-resident alveolar macrophages play a pivotal role in maintaining lung homeostasis by eliminating airborne pathogenic microorganisms. The process by which cells ingest particles >0.5 μm in diameter, such as bacteria (0.5 to 2 μm) and fungi (3 to 10 μm), is defined as phagocytosis, which is composed of recognition, engulfment, and subsequent steps of the digestion process [1, 2]. Pathogen recognition occurs by directly detecting microbe-specific molecular signatures, known as

pathogen-associated molecular patterns (PAMPs), using the corresponding pattern recognition receptors (PRRs), which activate downstream intracellular signaling that regulates cytoskeletal rearrangement and cell motility, leading to engulfment of pathogens [2–4]. As a result, efficient pathogen clearance necessitates sufficient expression of scavenger receptors as well as the continued concerted action of downstream signaling molecules. In addition to triggering phagocytosis, PAMPs induce the production of pro-inflammatory cytokines and chemokines via interactions with another family of PRRs, toll-like receptors (TLRs), resulting in the recruitment and activation of circulating phagocytes in the foci of infection and assisting the enhancement of macrophage phagocytosis [5–7].

However, unbridled inflammation is detrimental to tissue homeostasis, leading to organ failure if not properly treated. A typical example is the coronavirus disease 2019 (COVID-19), wherein critically ill patients are characterized by manifesting cytokine storm syndrome, resulting in respiratory failure and multiple organ failure [8, 9]. During viral infection, alveolar macrophages have been suggested to contribute to the alleviation of pneumonia by removing apoptotic epithelial cells and neutrophils from fighting viruses rather than by endocytosing viruses via pinocytosis and/or opsonization [10, 11]. Indeed, critically ill patients with COVID-19 are depleted of alveolar macrophages, which is accompanied by a remarkable increase in the proportion of pro-inflammatory monocyte-derived macrophages in bronchoalveolar lavage fluid [12]. Since the alternative type of phagocytosis, termed efferocytosis, is indispensable for preventing excessive inflammation during host defense against viral infection, failure of this protective action leads to the exacerbation of pneumonia from mild to life-threatening.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, has received much attention from researchers since its outbreak owing to its highly virulent and transmissible nature; notably, COVID-19 is not the only threat to people. Acute lower respiratory tract infections (LRTIs), caused predominantly by *Streptococcus pneumoniae* and influenza viruses, remain the deadliest epidemics [13–15] because the older population is particularly liable to develop pneumonia and thereby respiratory failure [16, 17]. The vulnerability of the elderly to acute LRTIs has been suggested to be associated with immune senescence. In line with this trend, age-associated declines in immune cell functions and their mechanisms have been discussed [18–20]. Moreover, age-related alterations in the tissue microenvironment deeply influence immune cell senescence [21–23], and recent progress has enabled the analysis of the reality of alveolar microenvironment degeneration with aging and its adverse effects on alveolar macrophages.

In this chapter, we summarized the physiological roles of alveolar macrophages in acute LRTIs, focusing on phagocytosis, pro-inflammatory responses, efferocytosis, and their regulatory mechanisms. This chapter then reviewed recent insights into age-associated dysfunction of alveolar macrophages and discussed their relevance to the vulnerability of the elderly population to acute LRTIs.
