T_H17 cells and corticosteroid insensitivity in severe asthma - 03/02/22

Doi : 10.1016/j.jaci.2021.12.769

Yan Xie, MD, PhD ^a, Peter W. Abel, PhD ^a, Thomas B. Casale, MD ^b,^⁎ , Yaping Tu, PhD ^a,^⁎
^a Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Neb
^b Department of Internal Medicine, University of South Florida School of Medicine, Tampa, Fla

^∗Corresponding author: Yaping Tu, PhD, Department of Pharmacology and Neuroscience, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178.Department of Pharmacology and NeuroscienceCreighton University School of Medicine2500 California PlazaOmahaNE68178^∗∗Thomas B. Casale, MD, Department of Internal Medicine, University of South Florida School of Medicine, Tampa, FL 33612.Department of Internal MedicineUniversity of South Florida School of MedicineTampaFL33612

Abstract

Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated T_H17 cell immune responses. T_H17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of T_H17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma.

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Key words : T_H17 cells, corticosteroid insensitivity, severe asthma, type 2 asthma, non–type 2 asthma, airway neutrophilia, IL-17, IL-6, RhoA, Rho-associated kinase

Abbreviations used : AHR, ASM, BATF, BCL6, BT, CSF3, GATA3, GR, IL1R1, IL6R, IL-6TS, IL-17RA, IL-17RC, ILC3, IRF4, MMP-9, NLRP3, PGA, ROCK, RORγt, RUNX1, SARP3, SOCS3, STAT3, Treg, T2

Plan

Neutrophilia in severe asthma

T_H17 cell differentiation

IL-17 cytokines and neutrophilia in severe asthma

Contribution of T_H17 cells and IL-17 cytokines to corticosteroid insensitivity in severe asthma

Therapeutic implications of targeting T_H17 cell responses in corticosteroid-insensitive asthma

Blocking IL-17A and IL-17RA

Blocking IL-6 and IL6R

Blocking IL-1β and its receptor

Blocking the transcription factor RORγt

Blocking RhoA/ROCK signaling pathways

Conclusion

	Supported in part by the National Institutes of Health (grants R01HL116849 [to Y. Tu and T.B. Casale] and 5R21ES029566 [to Y. Tu and P.W. Abel]) and the Nebraska State LB595 Research Program (to Y. Tu and P.W. Abel).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.