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Review
. 2022 May 12;9(1):21.
doi: 10.1186/s40779-022-00382-3.

Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis

Yun-Juan Nie  1 , Shuo-Hua Wu  2 , Ying-Hua Xuan  3 , Gen Yan  4
Affiliations
Review

Role of IL-17 family cytokines in the progression of IPF from inflammation to fibrosis

Yun-Juan Nie et al. Mil Med Res. .

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease with no established treatment and is characterized by progressive scarring of the lung tissue and an irreversible decline in lung function. Chronic inflammation has been demonstrated to be the pathological basis of fibrosis. Emerging studies have revealed that most interleukin-17 (IL-17) isoforms are essential for the mediation of acute and chronic inflammation via innate and adaptive immunity. Overexpression or aberrant expression of IL-17 cytokines contributes to various pathological outcomes, including the initiation and exacerbation of IPF. Here, we aim to provide an overview of IL-17 family members in the pathogenesis of IPF.

Keywords: IL-17 receptor; Idiopathic pulmonary fibrosis; Inflammation; Interleukin-17 (IL-17) family.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
IL-17 cytokines, receptors, and signaling. The IL-17 family is composed of six members, IL-17A–F, while the IL-17 receptor family is composed of five members, IL-17RA to IL-17RE (IL-17RD not shown). IL-17 signaling is activated through the binding of the IL-17 receptor complex to the adaptor protein Act1, which has been determined in IL-17C to recruit TRAF6 to drive the activation of downstream signaling pathways, MAPK, C/EBP, and NF-κB, contributing to the target gene expression as well as mediating the host defense and inflammatory response. IL-17R interleukin 17 receptor, TRAF6 tumor necrosis factor receptor-associated factor 6, C/EBP CCAAT/enhancer-binding protein, MAPK mitogen-activated protein kinase, NF-κB nuclear factor-kappaB, Act1 NF-κB activator 1, JNK JUN N-terminal kinase. ERK extracellular signal-regulated kinase, FN fibronectin, AP1 activator protein-1
Fig. 2
Fig. 2
Main cellular sources and targets of IL-17A and IL-17F in IPF. IL-17A and F can be produced by Th17 cells and other immune cells such as γδ T cells, natural killer cells, macrophages, neutrophils, and non-hematopoietic cells such as epithelial and endothelial cells. IL-17A can contribute to pulmonary fibrosis by EMT, fibroblast proliferation, and differentiation to myofibroblasts. IL-17F stimulates lung inflammation by contributing to the infiltration of neutrophils, macrophages, and lymphocytes as well as promoting the expression of proinflammatory cytokines such as IL-6 and CXC chemokines; however, the role of IL-17F in IPF remains unclear. NK natural killer cells, Th17 T helper cell 17, TNF-α tumor necrosis factor-α, IL-1 interleukin-1, IL-6 interleukin-6, TGF-β transforming growth factor-β, IL-8 interleukin-8, CCL2 C-C motif chemokine 2, CXCL1 C-X-C motif chemokine ligand 1, CXCL5 C-X-C motif chemokine 5, EMT epithelial-mesenchymal transition, α-SMA α-smooth muscle actin, ECM extracellular matrix, IPF idiopathic pulmonary fibrosis
Fig. 3
Fig. 3
Main cellular sources and targets of IL-17B in IPF. IL-17B is mainly secreted from the epithelium, neutrophils, and B cells. It plays an important role in mediating lung inflammation by stimulating the expression of the inflammatory mediators IL-6, IL-23, TNF-α, IL-1β, and chemokines from macrophages, neutrophils, and Th17 cells. IL-17B induces lung fibrosis by cooperating with TNF-α to stimulate the secretion of Th17-cell-promoting genes and neutrophil-recruiting genes. Th17 T helper cell 17, TNF-α tumor necrosis factor-α, IL-1β interleukin-1β, CXCL12 C-X-C motif chemokine ligand 12, CXCL13 C-X-C motif chemokine ligand 13, IPF idiopathic pulmonary fibrosis
Fig. 4
Fig. 4
Main cellular sources and targets of IL-17C in lung inflammatory response. IL-17C is expressed in various cells, including epithelial cells, Th17 cells, CD4+ T cells, DCs, and macrophages. It acts on multiple types of cells, including CD4+ T cells, macrophages, and neutrophils, playing an important role in lung inflammation. Definitive evidence has not been reported for the role of IL-17C in regulating pulmonary fibrosis. Th17 T helper cell 17, TNF-α tumor necrosis factor-α, IL-1β interleukin-1β, IPF idiopathic pulmonary fibrosis
Fig. 5
Fig. 5
Involvement of IL-17E in IPF. IL-17E is produced from injured epithelial cells. It acts on T cells, ILC2s, alveolar macrophages, DC and neutrophils, which can stimulate the secretion of cytokines such as IL-17E, IL-13, and TGF-β, drive lung fibrosis by mediating EMT, as well as recruit and activate lung fibroblasts. IL-17E can additionally activate a series of cell types, leading to lung inflammation, which is critical in the development of IPF. ILC2s type 2 innate lymphoid cells, IL-4 interleukin-4, IL-13 interleukin-13, TGF-β transforming growth factor-β, EMT epithelial–mesenchymal transition, ECM extracellular matrix, IPF idiopathic pulmonary fibrosis
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