The immune mechanisms of acute exacerbations of idiopathic pulmonary fibrosis

Abstract

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are the leading cause of mortality among patients with IPF. There is still a lack of effective treatments for AE-IPF, resulting in a hospitalization mortality rate as high as 70%-80%. To reveal the complicated mechanism of AE-IPF, more attention has been paid to its disturbed immune environment, as patients with IPF exhibit deficiencies in pathogen defense due to local immune dysregulation. During the development of AE-IPF, the classical stimulatory signals in adaptive immunity are inhibited, while the nonclassical immune reactions (Th17) are activated, attracting numerous neutrophils and monocytes to lung tissues. However, there is limited information about the specific changes in the immune response of AE-IPF. We summarized the immune mechanisms of AE-IPF in this review.

Keywords: Th17; acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF); acute lung injury; immune mechanism; macrophages.

Figure 1

The mechanism of idiopathic pulmonary fibrosis. In the niche of pulmonary fibrosis, macrophages are deficient in antigen recognition, phagocytosis, and antigen presentation. The surface markers of the fibrogenic macrophages are CD14⁺, SPP1⁺, CD36^high, and CD84^high. In such circumstances, Naïve CD4⁺ T lymphocytes are differentiated into Treg cells. TGFβ are mostly secreted by Treg, fibrogenic macrophages, and AECII. This figure was created by Figdraw (ID: UWSAI35444; www.figdraw.com). CCR2, C-C motif chemokine receptor-2; CCL2, C-C motif chemokine ligand-2; ICOS, inducible T-cell costimulatory; MHCII, major histocompatibility complex II; MMP9, matrix metalloproteinase-9; PD-1, programmed cell death protein-1; SIRPα, signal-regulatory protein-α; SPP1, osteopontin; STING, stimulator of interferon genes; TLR3, Toll-like receptor 3.

Figure 2

The mechanism of acute exacerbations of idiopathic pulmonary fibrosis. Environmental stress induces type II alveolar epithelial cells (AECII) and myofibroblasts to release GM-CSF and G-CSF, which are essential for the differentiation of hematopoietic progenitor cells (HPCs). With the help of chemokines, neutrophils and monocyte-derived macrophages (Mo-M) traffic to injured lung tissues and secrete acute inflammatory cytokines (IL-6, IL-23, and TNFα), which transform innate lymphocytes and Treg into Th17. Th17 secretes IL-17A and IL-22 acting on AECII and myofibroblasts to promote releasing GM-CSF and G-CSF. The positive feedback loop eventually leads to acute exacerbations of IPF. This figure was created by Figdraw (ID: AWRWUcba31; www.figdraw.com). AECII, type II alveolar epithelial cell; CCL2, C-C motif chemokine ligand-2; CXCL1, C-X-C motif chemokine ligand-1; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; HPC, hematopoietic progenitor cells; IL, interleukin; Mo-M, monocyte-derived macrophages; MDSC, myeloid-derived suppressor cells; MP, myeloid precursors; TGFβ, transforming growth factor-β; Th17, T helper cell 17; TNFα, tumor necrosis factor-α; Treg, regulatory T cells.