IL-37 Attenuates Lung Fibrosis by Inducing Autophagy and Regulating TGF-β1 Production in Mice

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and destructive lung disease with a poor prognosis resulting in a high mortality rate. IL-37 is an anti-inflammatory cytokine that inhibits innate and adaptive immunity by downregulating proinflammatory mediators and pathways. However, the exact role of IL-37 in lung fibrosis is unclear. In this study, we found that the IL-37 protein was expressed in alveolar epithelial cells (AECs) and alveolar macrophages in healthy controls but significantly reduced in patients with IPF. IL-37 significantly inhibited oxidative stress–induced primary mouse AEC death in a dose-dependent manner, and knockdown of IL-37 significantly potentiated human lung cancer–derived AEC (A549 cells) death. IL-37 attenuated constitutive mRNA and protein expression of fibronectin and collagen I in primary human lung fibroblasts. IL-37 inhibited TGF-β1–induced lung fibroblast proliferation and downregulated the TGF-β1 signaling pathway. Moreover, IL-37 enhanced beclin-1–dependent autophagy and autophagy modulators in IPF fibroblasts. IL-37 significantly decreased inflammation and collagen deposition in bleomycin-exposed mouse lungs, which was reversed by treatment with the autophagy inhibitor 3-methyladenine. Our findings suggested that a decrease in IL-37 may be involved in the progression of IPF and that IL-37 inhibited TGF-β1 signaling and enhancement of autophagy in IPF fibroblasts. Given its antifibrotic activity, IL-37 could be a therapeutic target in fibrotic lung diseases, including IPF.

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution

“…However, there was almost no detectable ApoE in BALF from the saline-treated control animals ( Figure 1, B and C). As expected, fibronectin (Fn) and osteopontin (OPN), 2 important profibrotic mediators (11,25), were also increased in the BALF from fibrotic lungs ( Figure 1C). In contrast to AMs, ApoE expression in alveolar epithelial cells (AECs) and fibroblasts (Fbs) from fibrotic lungs demonstrated little change ( Figure 1D).…”

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

“…On the other hand, as an anti-inflammatory cytokine, IL-37 was expressed in alveolar epithelial cells and alveolar macrophages in healthy controls but was significantly reduced in IPF patients. A recent study demonstrated that IL-37 decreased inflammation and inhibited collagen accumulation through the activation of autophagy in the BLM-induced mouse lung tissues 121 .…”

Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice

“…Decreased autophagy-mediated clearance of ECM proteins leads to their accumulation, contributing to the progression of fibrosis. Recently, Kim et al reported that the induction of autophagy alleviates BLM-induced lung fibrosis 21 . Thus, spermidine-mediated enhancement of autophagy may help resolve fibrosis.…”

“…Standard protocols for immunofluorescence microscopy were used as described previously 21 . Human primary fibroblasts were plated on cover-glass-bottom dishes and treated with or without with the indicated agents.…”