Macrophages: friend or foe in idiopathic pulmonary fibrosis?

Abstract

Idiopathic pulmonary fibrosis (IPF) is a prototype of lethal, chronic, progressive interstitial lung disease of unknown etiology. Over the past decade, macrophage has been recognized to play a significant role in IPF pathogenesis. Depending on the local microenvironments, macrophages can be polarized to either classically activated (M1) or alternatively activated (M2) phenotypes. In general, M1 macrophages are responsible for wound healing after alveolar epithelial injury, while M2 macrophages are designated to resolve wound healing processes or terminate inflammatory responses in the lung. IPF is a pathological consequence resulted from altered wound healing in response to persistent lung injury. In this review, we intend to summarize the current state of knowledge regarding the process of macrophage polarization and its mediators in the pathogenesis of pulmonary fibrosis. Our goal is to update the understanding of the mechanisms underlying the initiation and progression of IPF, and by which, we expect to provide help for developing effective therapeutic strategies in clinical settings.

Keywords: Alternatively activated (M2) macrophages; Classically activated (M1) macrophages; IPF; Macrophage polarization; Therapeutic strategies.

Fig. 1

Schematic diagram of macrophage subtypes. The M1 subtype is generally considered to be proinflammatory. The M2a subtype is induced by IL-4 and IL-13, which are critical mediators of allergic inflammation. The M2b and M2c subtypes predominately participate in tissue remodeling and fibrosis. BV, blood vessel; M0, monocyte; LPS, lipopolysaccharide; IL, interleukin

Fig. 2

Macrophages in the pathogenesis of pulmonary fibrosis. This schematic diagram demonstrates the mediators for modulation of macrophage subtypes and how macrophages contribute to IPF initiation and progression. M1 macrophages play an essential role for wound healing after alveolar epithelial injury, while M2 macrophages are require to resolve inflammatory responses in the lung, and IPF is a pathological outcome resulted from altered wound healing in response to persistent lung injury. Ly-6C (H), Ly-6C^high monocytes; MCS, mesenchymal stem cells; ILC2s, lymphoid type 2 cells; NKTs, natural killer T cells; MCU, mitochondrial calcium uniporter; CHOP, C/EBP homologous protein; IRAK-M, IL-1R–associated kinase-M; Arg 1, arginase 1; iNOS, inducible nitric oxide synthase