Mechanisms Targeting the Unfolded Protein Response in Asthma

Abstract

Lung cells are constantly exposed to various internal and external stressors that disrupt protein homeostasis. To cope with these stimuli, cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR). UPR stressors can impose greater protein secretory demands on the endoplasmic reticulum (ER), resulting in the development, differentiation, and survival of these cell types to meet these increasing functional needs. Dysregulation of the UPR leads to the development of the disease. The UPR and ER stress are involved in several human conditions, such as chronic inflammation, neurodegeneration, metabolic syndrome, and cancer. Furthermore, potent and specific compounds that target the UPR pathway are under development as future therapies. The focus of this review is to thoroughly describe the effects of both internal and external stressors on the ER in asthma. Furthermore, we discuss how the UPR signaling pathway is activated in the lungs to overcome cellular damage. We also present an overview of the pathogenic mechanisms, with a brief focus on potential strategies for pharmacological interventions.

Keywords: asthma; endoplasmic reticulum; endoplasmic reticulum stress; unfolded protein response.

Figure 1.

Unfolded protein response (UPR) signaling pathways. Proteins that are correctly folded in the endoplasmic reticulum (ER) are transferred to the Golgi apparatus for further modifications. Conversely, proteins that are misfolded after synthesis promote ER stress and activate three independent pathways (three different UPR arms) driven by ATF6, PERK, and IRE1. This counteracts abnormal protein synthesis, folding, and modification. Each UPR arm activates specific downstream transcription factors that are involved in the regulation of cellular proliferation, apoptosis, and protein translation pathways. ATF = activating transcription factor; Bip = binding immunoglobulin protein (a.k.a. GRP78); CHOP = C/EBP (CCAAT/enhancer-binding protein) homologous protein; eIF2α = eukaryotic translation initiation factor 2α; ERAD = ER-associated degradation; IRE1 = inositol-requiring enzyme 1α; p = phospho; PERK = protein kinase RNA-like ER kinase; RIDD = IRE1-dependent decay; RIP = regulated intramembrane proteolysis; XBP1 = X-box–binding protein 1.

Figure 2.

Asthma and UPR cross-talk. Allergens and viral or bacterial infections induce eosinophilia and T-helper cell type 2 (Th2; or type 2) inflammatory responses, which could trigger asthma. Stimuli such as aeroallergens, oxidative stress, bacteria, pollutants, and viral infections can also disrupt ER integrity and act as inducers of ER stress. Pathogenic factors in asthma trigger ER stress and UPR pathways contributing to apoptosis and fibrosis in the lung. They also activate mast cells and Th2 cells to drive inflammation, resulting in mucus hypersecretion, fibrosis, and bronchoconstriction after cytokine/chemokine release within the lung. DCs = dendritic cells.