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Review
. 2017 Nov 8;17(12):82.
doi: 10.1007/s11882-017-0751-9.

Endoplasmic Reticulum Stress and Allergic Diseases

Jae Seok Jeong  1 , So Ri Kim  1   2 , Seong Ho Cho  3 , Yong Chul Lee  4   5
Affiliations
Review

Endoplasmic Reticulum Stress and Allergic Diseases

Jae Seok Jeong et al. Curr Allergy Asthma Rep. .

Abstract

Purpose of review: In this review, we will integrate recent knowledge on endoplasmic reticulum (ER) stress and allergy, thereby highlighting the therapeutic potential of ER stress in the context of precision medicine for allergic diseases.

Recent findings: Emerging evidence suggests that allergic diseases are very heterogeneous having numerous endotypes. This leads to the new era of modern medicine, which assumes that a particular endotype-driven therapy, called precision medicine, would be more efficacious in a specific group of patients rather than in all patients. Currently, a dichotomy involving type 2/non-type 2 immune response underlies most of the studies on inflammatory and immunologic mechanisms of allergic disorders. Whereas there are several approved or investigational endotype-driven therapeutic agents targeting type 2 immune responses, investigation of mechanisms and endotype-driven interventions regarding non-type 2 immune response lags far behind. Considering that non-type 2 immune response may represent a significant proportion of allergic disease, particularly corticosteroid-resistant severe disease, defining a novel concept of endotype-driven approach may be essential. Recently, stress responses originate from the endoplasmic reticulum (ER) and the associated inflammatory molecular platform has been suggested as a crucial player of immune and inflammatory responses. This implies that ER stress-related pathways may represent a new endotype-driven therapeutic strategy in the treatment of allergic diseases.

Keywords: Allergic diseases; Biomarker; ER stress; Endoplasmic reticulum stress; Inflammation; Precision medicine.

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Conflict of interest statement

Conflict of Interest

Dr. Lee reports grants from The Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea, grants from The Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, Information and Communication Technology and Future Planning, grants from Biomedical Research Institute, Chonbuk National University Hospital, during the conduct of the study. The other authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Figures

Fig. 1
Fig. 1
Interconnection between endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathways and mitochondria-NLRP3 inflammasome in allergic diseases. The accumulation of misfolded/unfolded proteins in the ER lumen activates UPR, which is mediated by three ER transmembrane stress sensors including inositol-requiring 1α (IRE1α), double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6). In a condition of ER stress, an abundant ER chaperone, glucose-regulated protein 78 (GRP78), preferentially associates with accumulated misfolded/unfolded proteins. Dissociation of GRP78 from the ER stress sensors, or direct engagement of misfolded/unfolded protein to IRE1α, transmits signals about folding status of ER to the cytosol and nucleus. The canonical aspect of UPR regulates the secretory pathway of ER and attempts to reduce ER stress through reducing demand of protein folding, promoting ER-associated degradation (ERAD) and gene expression involved in cell survival (e.g., autophagy), and increasing ER chaperones to defend cells from ER stress. If cells fail to resolve ER stress, these adaptive responses will initiate apoptosis, mainly through C/EBP homologous protein (CHOP). In addition to this canonical aspect of UPR pathways, close interrelationship between ER/UPR pathways and cellular inflammatory platforms including mitochondria (e.g., oxidative stress from mitochondrial reactive oxygen species (ROS); mtROS) and NLRP3 inflammasome (an interleukin-1β producing platform) may be critically implicated in a unique form of corticosteroid-resistant type 2 allergic immune response
Fig. 2
Fig. 2
A proposed endotype-driven approach based on endoplasmic reticulum (ER) stress in allergic diseases. ER stress and unfolded protein response (UPR) pathways are closely associated with allergic immune responses involving various important cell types (e.g., epithelial cells, dendritic cells, T and B cells, granulocytes, and macrophages) and inflammatory pathways (e.g., ER stress-associated nuclear factor (NF)-κB signaling, UPR-dependent secretion of interleukin (IL)-6 and tumor necrosis factor (TNF), and NLRP3 inflammasome-mediated IL-1β production). Through analyzing ER stress-associated molecular profiles including ER stress markers (e.g., GRP78 and CHOP), UPR pathway components, and related inflammatory platforms (e.g., mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome) in blood, sputum, or tissue biopsy specimen from allergic patients, we may design a novel endotype-based approach in association with ER stress
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