Targeting the phosphorylation site of myristoylated alanine-rich C kinase substrate alleviates symptoms in a murine model of steroid-resistant asthma

Chien Neng Wang, Yu Chao Lin, Bo Chun Chang, Ching-Hsien Chen, Reen Wu, Chen Chen Lee

Research output: Contribution to journalArticle

Abstract

Background and Purpose: Myristoylated alanine-rich C kinase substrate (MARCKS), a PKC substrate, facilitates mucus production and neutrophil migration. However, the effects of therapeutic procedures targeting the phosphorylation site of MARCKS on steroid-resistant asthma and the mechanisms underlying such effects have not yet been investigated. We designed a peptide that targets the MARCKS phosphorylation site (MPS peptide) and assessed its therapeutic potential against steroid-resistant asthma. Experimental Approach: Mice were sensitized with ovalbumin (OVA), alum, and challenged with aerosolized OVA five times a week for 1 month. The mice were intratracheally administered MPS peptides three times a week, 1 hr before OVA challenge. Asthma symptoms and cell profiles in the bronchoalveolar lavage were assessed, and key proteins were analysed using Western blotting. Key Results: Phosphorylated (p)-MARCKS was highly expressed in inflammatory and bronchial epithelial cells in OVA-immunized mice. MPS peptide reduced eosinophils, neutrophils, mucus production, collagen deposition, and airway hyper-responsiveness. Dexamethasone (Dexa) did not alleviate steroid-resistant asthma symptoms. MPS peptide caused a decrease in p-MARCKS, nitrotyrosine and the expression of oxidative stress enzymes, NADPH oxidase dual oxidase 1 and inducible NOS, in lung tissues. Compared to Dexa, MPS peptides inhibited C5a production and attenuated IL-17A and KC production in the airway more effectively, thus suppressing asthma symptoms. Conclusions and Implications: Our findings indicate that targeting MARCKS phosphorylation through MPS treatment may inhibit neutrophilic inflammation and relieve asthma symptoms, thereby highlighting its potential as a therapeutic agent for steroid-resistant asthma.

Original languageEnglish (US)
Pages (from-to)1122-1134
Number of pages13
JournalBritish Journal of Pharmacology
Volume176
Issue number8
DOIs
StatePublished - Apr 1 2019

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Asthma
Steroids
Phosphorylation
Peptides
Ovalbumin
Mucus
Dexamethasone
Respiratory Hypersensitivity
Neutrophils
Interleukin-17
NADPH Oxidase
Bronchoalveolar Lavage
Therapeutic Uses
myristoylated alanine-rich C kinase substrate
Eosinophils
Oxidoreductases
Oxidative Stress
Collagen
Therapeutics
Western Blotting

ASJC Scopus subject areas

  • Pharmacology

Cite this

Targeting the phosphorylation site of myristoylated alanine-rich C kinase substrate alleviates symptoms in a murine model of steroid-resistant asthma. / Wang, Chien Neng; Lin, Yu Chao; Chang, Bo Chun; Chen, Ching-Hsien; Wu, Reen; Lee, Chen Chen.

In: British Journal of Pharmacology, Vol. 176, No. 8, 01.04.2019, p. 1122-1134.

Research output: Contribution to journalArticle

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abstract = "Background and Purpose: Myristoylated alanine-rich C kinase substrate (MARCKS), a PKC substrate, facilitates mucus production and neutrophil migration. However, the effects of therapeutic procedures targeting the phosphorylation site of MARCKS on steroid-resistant asthma and the mechanisms underlying such effects have not yet been investigated. We designed a peptide that targets the MARCKS phosphorylation site (MPS peptide) and assessed its therapeutic potential against steroid-resistant asthma. Experimental Approach: Mice were sensitized with ovalbumin (OVA), alum, and challenged with aerosolized OVA five times a week for 1 month. The mice were intratracheally administered MPS peptides three times a week, 1 hr before OVA challenge. Asthma symptoms and cell profiles in the bronchoalveolar lavage were assessed, and key proteins were analysed using Western blotting. Key Results: Phosphorylated (p)-MARCKS was highly expressed in inflammatory and bronchial epithelial cells in OVA-immunized mice. MPS peptide reduced eosinophils, neutrophils, mucus production, collagen deposition, and airway hyper-responsiveness. Dexamethasone (Dexa) did not alleviate steroid-resistant asthma symptoms. MPS peptide caused a decrease in p-MARCKS, nitrotyrosine and the expression of oxidative stress enzymes, NADPH oxidase dual oxidase 1 and inducible NOS, in lung tissues. Compared to Dexa, MPS peptides inhibited C5a production and attenuated IL-17A and KC production in the airway more effectively, thus suppressing asthma symptoms. Conclusions and Implications: Our findings indicate that targeting MARCKS phosphorylation through MPS treatment may inhibit neutrophilic inflammation and relieve asthma symptoms, thereby highlighting its potential as a therapeutic agent for steroid-resistant asthma.",
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