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

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 effectshave 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 hyperresponsiveness. 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.

Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases

“…The full activity of p22 phox is also required for MARCKS phosphorylation at Ser152 and Ser156 regulatory residues [ 116 ]. However, while MARCKS phosphorylation at Ser159 and Ser163 is mainly involved in inflammatory diseases [ 117 , 118 ], phosphorylation at Ser152, Ser156, and 170 residues seems to be involved in the regulation of cytoskeletal reorganization [ 116 ].…”

MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer

“…Notably, treatment with 20% CSE resulted in an approximately 1.9-fold increase of phospho-p65 expression and 2.3-fold decease of IκBα level (Figure 5 B). We previously identified a small peptide, the MPS peptide, which targets the MARCKS PSD and inhibits MARCKS-mediated functions with no cytotoxic effect on normal human epithelial cells 13 , 18 , 26 , 27 . Through treatment with 50 μM MPS peptide in lung cancer cells exposed to 20% CSE, we confirmed that MPS peptide had an inhibitory effect on smoke-enhanced MARCKS phosphorylation in both CL1-0 and H292 cells (Figure 5 C).…”

Detection of Immune Microenvironment Changes and Immune‐Related Regulators in Langerhans Cell Histiocytosis Bone Metastasis

“…In our research, by enrichment analysis and partial correlation analysis, we found that MARCKS was highly correlated with hub genes such as CD74 and immune cells such as DCs, which are responsible for LCH. Since MARCKS is currently viewed as a potential target for immunotherapy and chemosensitivity, it is reasonable to believe that it will also be a potential therapeutic target for LCH [ 33 , 34 ].…”