Mechanisms of Non-type 2 Asthma

Overview

Journal Curr Opin Immunol

Publisher Elsevier

Specialty Allergy & Immunology

Date 2020 Nov 7

PMID 33160187

Citations 51

Authors

Stephanie N Hudey

Dennis K Ledford

Juan Carlos Cardet

Affiliations

Soon will be listed here.

Abstract

Non-type 2 inflammation (Non-T2)-mediated asthma is difficult to define due to lack of signature biomarkers. It exists in the absence of T2-high or eosinophilic inflammation and includes neutrophilic and paucigranulocytic subtypes. Several cell types and cytokines, including Th1, Th17, IL-6, and IL-17, contribute to mechanisms of non-T2 asthma. Neutrophil extracellular traps (NETs) and inflammasome activation likely play a role in severe neutrophilic asthma. Several mechanisms lead to uncoupling of airway hyperresponsiveness and remodeling from airway inflammation in paucigranulocytic asthma. Recent research on transcriptomics and proteomics in non-T2 asthma is discussed in this review. Investigations of specific drug therapies for non-T2 asthma have been disappointing, and remain an important area for future clinical studies.

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References

Kuo C, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I . T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017; 49(2). DOI: 10.1183/13993003.02135-2016. View

Jiang H, Xie Y, Abel P, Wolff D, Toews M, Panettieri Jr R . Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma. Am J Respir Cell Mol Biol. 2014; 53(1):42-9. PMC: 4566111. DOI: 10.1165/rcmb.2014-0319OC. View

Raundhal M, Morse C, Khare A, Oriss T, Milosevic J, Trudeau J . High IFN-γ and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015; 125(8):3037-50. PMC: 4563754. DOI: 10.1172/JCI80911. View

Dragunas G, Woest M, Nijboer S, Bos S, van Asselt J, de Groot A . Cholinergic neuroplasticity in asthma driven by TrkB signaling. FASEB J. 2020; 34(6):7703-7717. PMC: 7302963. DOI: 10.1096/fj.202000170R. View

Massoud A, Charbonnier L, Lopez D, Pellegrini M, Phipatanakul W, Chatila T . An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med. 2016; 22(9):1013-22. PMC: 5014738. DOI: 10.1038/nm.4147. View

Papayannopoulos V . Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2017; 18(2):134-147. DOI: 10.1038/nri.2017.105. View

Ricciardolo F, Sorbello V, Folino A, Gallo F, Massaglia G, Favata G . Identification of IL-17F/frequent exacerbator endotype in asthma. J Allergy Clin Immunol. 2016; 140(2):395-406. DOI: 10.1016/j.jaci.2016.10.034. View

Peters M, Mauger D, Ross K, Phillips B, Gaston B, Cardet J . Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency. Am J Respir Crit Care Med. 2020; 202(7):973-982. PMC: 7528796. DOI: 10.1164/rccm.201909-1813OC. View

Schleich F, Zanella D, Stefanuto P, Bessonov K, Smolinska A, Dallinga J . Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma. Am J Respir Crit Care Med. 2019; 200(4):444-453. DOI: 10.1164/rccm.201811-2210OC. View

10.

Madigan L, Wong G, Gordon E, Chen W, Balenga N, Koziol-White C . RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice. Am J Respir Cell Mol Biol. 2017; 58(1):89-98. PMC: 5800898. DOI: 10.1165/rcmb.2017-0109OC. View

11.

Neveu W, Allard J, Dienz O, Wargo M, Ciliberto G, Whittaker L . IL-6 is required for airway mucus production induced by inhaled fungal allergens. J Immunol. 2009; 183(3):1732-8. PMC: 2929571. DOI: 10.4049/jimmunol.0802923. View

12.

Kim R, Pinkerton J, Essilfie A, Robertson A, Baines K, Brown A . Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma. Am J Respir Crit Care Med. 2017; 196(3):283-297. DOI: 10.1164/rccm.201609-1830OC. View

13.

Kasaian M, Lee J, Brennan A, Danto S, Black K, Fitz L . Proteomic analysis of serum and sputum analytes distinguishes controlled and poorly controlled asthmatics. Clin Exp Allergy. 2018; 48(7):814-824. DOI: 10.1111/cea.13151. View

14.

Frossard N, Freund V, Advenier C . Nerve growth factor and its receptors in asthma and inflammation. Eur J Pharmacol. 2004; 500(1-3):453-65. DOI: 10.1016/j.ejphar.2004.07.044. View

15.

Watanabe T, Fajt M, Trudeau J, Voraphani N, Hu H, Zhou X . Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes. Am J Respir Cell Mol Biol. 2015; 53(6):844-52. PMC: 4742942. DOI: 10.1165/rcmb.2015-0015OC. View

16.

Busse W, Holgate S, Kerwin E, Chon Y, Feng J, Lin J . Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013; 188(11):1294-302. DOI: 10.1164/rccm.201212-2318OC. View

17.

I Abdel-Aziz M, Brinkman P, Vijverberg S, Neerincx A, Riley J, Bates S . Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months. J Allergy Clin Immunol. 2020; 147(1):123-134. DOI: 10.1016/j.jaci.2020.04.018. View

18.

Xie Y, Jiang H, Nguyen H, Jia S, Berro A, Panettieri Jr R . Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness. J Allergy Clin Immunol. 2012; 130(4):968-76.e3. DOI: 10.1016/j.jaci.2012.05.004. View

19.

Rossios C, Pavlidis S, Hoda U, Kuo C, Wiegman C, Russell K . Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J Allergy Clin Immunol. 2017; 141(2):560-570. DOI: 10.1016/j.jaci.2017.02.045. View

20.

Li X, Hastie A, Peters M, Hawkins G, Phipatanakul W, Li H . Investigation of the relationship between IL-6 and type 2 biomarkers in patients with severe asthma. J Allergy Clin Immunol. 2019; 145(1):430-433. PMC: 7469890. DOI: 10.1016/j.jaci.2019.08.031. View