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A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”

1
Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju 54907, Korea
2
Research Institute of Clinical Medicine of Chonbuk National University–Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 54907, Korea
3
Division of Allergy and Immunology, Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33618, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 713; https://doi.org/10.3390/ijms20030713
Received: 14 January 2019 / Revised: 28 January 2019 / Accepted: 2 February 2019 / Published: 7 February 2019
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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Abstract

Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma. View Full-Text
Keywords: severe asthma; heterogeneity; endotype; endoplasmic reticulum stress severe asthma; heterogeneity; endotype; endoplasmic reticulum stress
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Jeong, J.S.; Kim, S.R.; Cho, S.H.; Lee, Y.C. A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”. Int. J. Mol. Sci. 2019, 20, 713.

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