Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) has attracted extensive attention for its unexplained progressive lung scarring, short median survival and its unresponsiveness to traditional therapies. Despite extensive studies, the mechanisms underlying IPF pathoetiologies, however, remain poorly understood. Recent advances delineated a potential function of endoplasmic reticulum (ER) stress in meeting the need of fibrotic response, which pinpointed a critical role for the unfolded protein response (UPR) pathways in IPF pathogenesis. In this review, we highlight the effect of ER stress and the activation of UPR on the survival, differentiation, function and proliferation of major profibrotic cells in lung tissues during the course of IPF, and discuss the feasibility whether targeting UPR components could be an orientation for developing effective therapeutic strategies against this devastating disorder in clinical settings.

Keywords: ER stress; IPF; UPR; pathogenesis; profibrotic cells.

Figure 1

Overview of fibrogenesis in IPF. In the early phase of fibrogenesis, epithelial and/or endothelial damage caused by a variety of irritants can initiate an anti-fibrinolytic coagulation cascade, temporarily plugging the damaged vessel with platelets and fibrin-rich clots to quickly restore homeostasis. Meanwhile, thrombin and the injured epithelium can directly evoke fibroblast activation and promote fibroblast differentiation into collagen-producing myofibroblasts. After a short period of time, clot-forming responses rapidly progress into a phase, in which many inflammatory cells such as macrophages, neutrophils, and lymphocytes are recruited into the injured site, where they secretecopious amount of cytokines to eliminate the inciting factor whilst activating the resident quiescent fibroblasts into myofibroblasts. However, once an imbalance in cytokine production coupled with dysregulated cellular recruitment occurs, a normal wound-healing response can switch into a pathological fibrotic reaction, ultimately resulting in pulmonary fibrosis. MAC = macrophages, BAS = basophils, NEU = neutrophils, MC = mast cells, EOS = eosinophils.

Figure 2

Schematic illustration of ER stress and the activation of three UPR pathways. Under stressed condition, BiP dissociates from the ER stress sensors owing to aggregation of unfold or misfolded proteins in ER lumen, which releases the stress sensors to initiate downstream signaling. Activated PERK undergoes autophosphorylation and dimerization and subsequently inhibits ribosome assembly by phosphorylating the α-subunit of eukaryotic translational initiation factor 2 (eIF2α). Once becomes phosphorylated, eIF2α not only suppresses protein translation, but also upregulates the expression of activating transcription factor 4 (ATF4), which would induce the transcription of protective genes DNA damage-inducible protein 34 (GADD34) as well as the pro-apoptotic gene encoding C/EBP homologous protein (CHOP). In general, CHOP is often produced in the terminal unfolded protein response (UPR) to induce apoptosis. After dissociating from BiP, ATF6α translocates to the Golgi apparatus, where it is cleaved by site 1 protease (S1P) and S2P into an NH2 terminal domain and a cytosolic fragment (ATF6p50). ATF6p50 is then transported into the nucleus and activates the transcription of several ER proteins such as X-box binding protein 1 (XBP1), calreticulin, calnexin, disulfide isomerase and CHOP. Upon activation, IRE-1α dimerizes and cleaves XBP1 into its spliced form, which then acts as a transcription factor of many stress proteins to enlarge the protein-folding capacity of ER, and to induce the expression of ER associated degradation (ERAD)-related proteins such as ER degradation enhancing α-mannosidase-like protein (EDEM).

Figure 3

ER stress modulates the function and phenotype of profibrotic cells during the development of pulmonary fibrosis. This schematic paradigm demonstrates how ER stress modulates the function and phenotype of profibrotic cells contributing to IPF pathogenesis. It is believed that ER stress can drive alveolar epithelial cell apoptosis, epithelial-to-mesenchymal transition (EMT), macrophages polarization, and (myo)fibroblasts activation, by which it promotes pulmonary fibrosis.