The Role of Macrophages in the Development of Acute and Chronic Inflammatory Lung Diseases

Abstract

Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.

Keywords: M1/M2 polarization; acute/chronic inflammatory diseases; cytokines; macrophages.

Figure 1

The macrophage population in the lung. Alveolar macrophages (AMs) and interstitial macrophages (IMs) reside in the lungs. AMs are in close contact with the epithelial cells of alveoli, and IMs reside in the parenchyma between the microvascular endothelium and alveolar epithelium. When AMs are damaged, circulating monocytes in the capillaries are then recruited to the lungs and transformed into AM-like cells.

Figure 2

The role of macrophages in ALI/ARDS. Bacterial infection induces the development of ALI and ARDS. Under these conditions, AMs can be classified as M1 and M2 macrophages. Th1 cytokines, such as IFN-γ, and lipopolysaccharide (LPS), induce M1 phenotype macrophages, which produce iNOS, TNF-α, IL-6, and MCP-1, which are responsible for the pro-inflammatory, chemotaxis, radical formation, matrix degradation, and antimicrobial activities during the pathogenesis of ALI/ARDS. Th2 cytokines, such as IL-4 and IL-13, induce M2 phenotype macrophages (divided into M2a, M2b, M2c, and M2d), and these cells produce anti-inflammatory molecules, such as IL-10 and TGF-β, in ALI/ARDS.

Figure 3

The role of macrophages in allergic asthma. Antigen-presenting cells (APCs) recognize allergens and initiate the allergic cascade. Under these conditions, naïve CD4+ T cells differentiate into Th2 cells. Th2 cell-mediated IL-4 and IL-13 generation lead to the induction of M2 phenotype macrophages. M2 macrophages are classified into subdivisions (M2a, M2b, and M2c). Macrophage-derived inflammatory cytokines and chemokines promote eosinophil recruitment and allergic airway inflammatory responses. Macrophage-derived TGF-β also promotes the proliferation of airway smooth muscle cells and fibrosis. IL-5 induces eosinophil influx and activation. Eosinophil-derived CCL11 leads to eosinophil recruitment. IL-13 induces goblet cell hyperplasia and mucus hypersecretion. This increased secretion contributes to the airflow obstruction. Airway epithelial cell-derived IL-33 promotes levels of M2 macrophages and stimulates mast cells which, in turn, leads to the generation of histamine and leukotrienes. This series of processes leads to airway inflammation and remodeling in addition to mucus overproduction in allergic asthma.

Figure 4

The macrophages in chronic obstructive pulmonary disease (COPD). Tobacco smoking causes airway inflammation, emphysema, and airway remodeling. Neutrophils and macrophages are key inflammatory cells in the pathogenesis of COPD. Neutrophil-derived ROS and elastase promote mucus hypersecretion and emphysema. Macrophages secrete inflammatory cytokines and chemokines, promoting neutrophil recruitment and levels of neutrophil-associated molecules, such as elastase and ROS. Macrophages also are involved in fibrotic remodeling.