Roles of sirtuins in asthma

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Abstract

Sirtuins are nicotinamide adenine dinucleotide (NAD ⁺)-dependent lysine deacylases and deacetylases that participate in a variety of cellular processes, including transcriptional activity, energy metabolism, DNA damage response, inflammation, apoptosis, autophagy, and oxidative stress. As a result, sirtuins are linked to multiple pathophysiological processes, such as cardiovascular diseases, metabolic diseases, autoimmune diseases, infectious diseases, and respiratory diseases. Asthma is the most common respiratory disease, which is characterized by airway inflammation and airway remodeling. Accumulating evidence has indicated that sirtuins are involved in the pathogenesis of asthma. Furthermore, some studies have suggested that sirtuin modulators are potential agents for the treatment of asthma via alteration of the expression or activity of sirtuins. In this review, we illustrate the role of sirtuins in asthma, discuss related molecular mechanisms, and evaluate the sirtuins-targeted therapy for asthma.

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T-helper type 2-driven inflammation defines major subphenotypes of asthma.

Prescott G Woodruff, Barmak Modrek, David F Choy … (2009)

T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination. Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

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Asthma

Alberto Papi, Christopher Brightling, Søren Pedersen … (2018)

Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti-inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed.

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Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase.

Bin He, J. Yu, Hening Lin … (2011)

Silent information regulator 2 (Sir2) proteins (sirtuins) are nicotinamide adenine dinucleotide-dependent deacetylases that regulate important biological processes. Mammals have seven sirtuins, Sirt1 to Sirt7. Four of them (Sirt4 to Sirt7) have no detectable or very weak deacetylase activity. We found that Sirt5 is an efficient protein lysine desuccinylase and demalonylase in vitro. The preference for succinyl and malonyl groups was explained by the presence of an arginine residue (Arg(105)) and tyrosine residue (Tyr(102)) in the acyl pocket of Sirt5. Several mammalian proteins were identified with mass spectrometry to have succinyl or malonyl lysine modifications. Deletion of Sirt5 in mice appeared to increase the level of succinylation on carbamoyl phosphate synthase 1, which is a known target of Sirt5. Thus, protein lysine succinylation may represent a posttranslational modification that can be reversed by Sirt5 in vivo.

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Author and article information

Contributors

Guochao Shi: shiguochao@hotmail.com

Journal

Journal ID (nlm-ta): Respir Res

Journal ID (iso-abbrev): Respir Res

Title: Respiratory Research

Publisher: BioMed Central (London )

ISSN (Print): 1465-9921

ISSN (Electronic): 1465-993X

Publication date (Electronic): 18 September 2022

Publication date PMC-release: 18 September 2022

Publication date (Print): 2022

Volume: 23

Electronic Location Identifier: 251

Affiliations

[1 ]GRID grid.412277.5, ISNI 0000 0004 1760 6738, Department of Respiratory and Critical Care Medicine, , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, ; Shanghai, People’s Republic of China

[2 ]GRID grid.412277.5, ISNI 0000 0004 1760 6738, Institute of Respiratory Diseases, , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, ; Shanghai, People’s Republic of China

[3 ]GRID grid.412277.5, ISNI 0000 0004 1760 6738, Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, , Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, ; Shanghai, People’s Republic of China

Article

Publisher ID: 2175

DOI: 10.1186/s12931-022-02175-7

PMC ID: 9482752

PubMed ID: 36117172

SO-VID: 4b1c987b-2a5d-4414-9812-491ab7c0dfd5

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 10 June 2022

Date accepted : 9 September 2022

Funding

Funded by: Shanghai Sailing Program

Award ID: 22YF1424800

Award Recipient : Yahui Liu

Funded by: National Natural Science Foundation of China

Award ID: 82170023

Award Recipient : Guochao Shi

Custom metadata

ScienceOpen disciplines: Respiratory medicine

Keywords: sirtuins,asthma,sirt1,modulators

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ScienceOpen disciplines: Respiratory medicine

Keywords: sirtuins, asthma, sirt1, modulators

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Roles of sirtuins in asthma

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 96

T-helper type 2-driven inflammation defines major subphenotypes of asthma.

Asthma

Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase.

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