Macrophages in Lung Injury, Repair, and Fibrosis

Abstract

Fibrosis progression in the lung commonly results in impaired functional gas exchange, respiratory failure, or even death. In addition to the aberrant activation and differentiation of lung fibroblasts, persistent alveolar injury and incomplete repair are the driving factors of lung fibrotic response. Macrophages are activated and polarized in response to lipopolysaccharide- or bleomycin-induced lung injury. The classically activated macrophage (M1) and alternatively activated macrophage (M2) have been extensively investigated in lung injury, repair, and fibrosis. In the present review, we summarized the current data on monocyte-derived macrophages that are recruited to the lung, as well as alveolar resident macrophages and their polarization, pyroptosis, and phagocytosis in acute lung injury (ALI). Additionally, we described how macrophages interact with lung epithelial cells during lung repair. Finally, we emphasized the role of macrophage polarization in the pulmonary fibrotic response, and elucidated the potential benefits of targeting macrophage in alleviating pulmonary fibrosis.

Keywords: acute lung injury; lung epithelial cells; lung repair; macrophage; pulmonary fibrosis.

Figure 1

Macrophages in lung injury and repair. Lung tissue resident macrophages and monocyte-derived macrophages can be polarized into classically activated macrophage (M1) phenotype stimulated by LPS and interferon gamma (IFNγ), or into alternatively activated macrophage (M2) phenotype in presence of IL-4 and IL-13. TNFα-stimulated gene-6 (TSG6) and MCP-induced protein 1 (MCPIP1) can convert macrophages from M1 to M2 phenotype. M1 macrophages secrete pro-inflammatory cytokines, such as IL-6, TNFα, leading to enhanced lung injury. Impaired phagocytosis and pyroptosis of alveolar macrophages result in exacerbated lung injury. M2 macrophages produce arginase and contribute to alveolar type 2 cells (AT2) proliferation, resulting in tissue repair after injury. The protein ‘found in inflammatory zone’ (Fizz1) expressed by AT2 cells recruits monocyte-derived macrophages and promotes fibroblast proliferation. Interstitial macrophages derived IL-1β hinders AT1 differentiation.

Figure 2

Macrophage in lung fibrosis. Fizz1 expressed by AT2 cells recruits monocyte-derived macrophages and promotes fibroblast activation and proliferation in the lung. Monocyte-derived macrophages secrete macrophage colony-stimulating factor (M-CSF) in an autocrine manner for self-maintenance, and produce platelet-derived growth factor subunit A (PDGFA), arginase 1, matrix metallopeptidase 13 (MMP13) to promote fibrotic process. Both alveolar macrophages and monocyte-derived macrophages can be polarized into M2 phenotype. M2 macrophages produce TGF-β1, inducing the differentiation of fibroblasts into myofibroblasts. Overexpression of IL-4 and IL-10 derived from M2 macrophages also contributes to lung fibrosis.