Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense

Abstract

Respiratory viral infections continue to cause pandemic and epidemic outbreaks in humans and animals. Under steady-state conditions, alveolar macrophages (AlvMϕ) fulfill a multitude of tasks in order to maintain tissue homeostasis. Due to their anatomic localization within the deep lung, AlvMϕ are prone to detect and react to inhaled viruses and thus play a role in the early pathogenesis of several respiratory viral infections. Here, detection of viral pathogens causes diverse antiviral and proinflammatory reactions. This fact not only makes them promising research targets, but also suggests them as potential targets for therapeutic and prophylactic approaches. This review aims to give a comprehensive overview of the current knowledge about the role of AlvMϕ in respiratory viral infections of humans and animals.

Keywords: SARS-CoV-2; alveolar macrophages; influenza A virus; innate immunity; respiratory infection; respiratory syncytial virus; tissue-resident macrophages.

Figure 4

Hypothesized routes of canine distemper virus (CDV) entry and release in the pulmonary system. (A) CDV is taken up by SLAM⁺ alveolar macrophages, and bypasses the epithelium or enters epithelial cells directly, via micropinocytosis. (B) Professional antigen-presenting cells present CDV antigen to peripheral blood mononuclear cells (PBMCs), in particular lymphocytes. (C) CDV replication takes place in regional lymph nodes before dissemination to distant lymphoid tissues. (D) During secondary viremia, CDV is transported to the lung. (E) CDV-infected immune cells migrate to the basolateral side of the epithelium. (F) CDV enters epithelial cells via cellular adhesion molecule nectin-4. (G) CDV is released at the apical side to the lumen and propelled rostrally via the mucus layer, ciliary beating, and coughing. Adapted from “Hypothesized routes of CDV entry and release in the pulmonary airway system.” by Elisa Chludzinski, licenced under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/, accessed on 1 December 2024) [420].

Figure 1

Interaction of alveolar macrophages (AlvMϕ) with their anatomical niche under homeostatic conditions. (A). AlvMϕ metabolize and recycle alveolar surfactant. (B) AlvMϕ clear apoptotic cells from the alveolar space (efferocytosis) and promote epithelial repair. (C) Suppressor of cytokine signaling (SOCS) protein secretion by AlvMϕ influences epithelial responsiveness to cytokines and is enhanced by epithelial-derived Prostaglandin E₂ (PGE₂). (D) Regulatory interactions between AlvMϕ and epithelial cells secure the tight regulation of AlvMϕ inflammatory reactions via interleukin 10 (IL-10), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor-β (TGF-β), and CD200. (E) Direct intercellular transduction via gap junction formation between AlvMϕ and epithelial cells and Ca²⁺ waves. (F). AlvMϕ mediate suppression of antigen presentation by dendritic cells and T cell proliferation via TGF-β and prostaglandin signaling.

Figure 2

Suggested role of alveolar macrophages (AlvMϕ) in SARS-CoV-2 pathogenesis. (A) Activation of AlvMϕ by contact with viral products and subsequent induction of proinflammatory and chemotactic cytokines and chemokines. (B) Recruitment of T cells and inflammatory monocytes from the peripheral blood. (C) T cell-derived interferon-γ (IFN-γ) further stimulates AlvMϕ activation. (D) This hyperinflammatory microenvironment favors dysregulation and death of AlvMϕ. (E) Replenishing the lost AlvMϕ; interferon-stimulated, recruited monocytes accumulate within the alveolus and may cause tissue damage. (F). In convalescing patients, recruited monocytes differentiate into homeostatic AlvMϕ and alveolar homeostasis is restored.

Figure 3

Detection of CDV nucleoprotein (NP) in Iba1⁺ airway histiocytes (white arrows). The photomicrograph by Elisa Chludzinski was published in “Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection” licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/, accessed on 1 December 2024) [408].