Abstract
Annexin-A1 (AnxA1) and its N-terminal derived peptide Ac2-26 regulate the inflammatory response in several experimental models of disorders. This study evaluated the effect of endogenous AnxA1 and its N-terminal peptide Acetyl 2-26 (Ac2-26) on allergic asthma triggered by house dust mite (HDM) extract in mice. ANXA1−/− and wildtype (WT) mice were exposed to intranasal instillation of HDM every other day for 3 weeks, with analyses performed 24 h following the last exposure. Intranasal administration of peptide Ac2-26 was performed 1 h before HDM, beginning 1 week after the initial antigen application. ANXA1−/− mice stimulated with HDM showed marked exacerbations of airway hyperreactivity (AHR), eosinophil accumulation, subepithelial fibrosis, and mucus hypersecretion, all parameters correlating with overexpression of cytokines (IL-4, IL-13, TNF-α, and TGF-β) and chemokines (CCL11/eotaxin-1 and CCL2/MCP-1). Intranasal treatment with peptide Ac2-26 decreased eosinophil infiltration, peribronchiolar fibrosis, and mucus exacerbation caused by the allergen challenge. Ac2-26 also inhibited AHR and mediator production. Collectively, our findings show that the AnxA1-derived peptide Ac2-26 protects against several pathological changes associated with HDM allergic reaction, suggesting that this peptide or related AnxA1-mimetic Ac2-26 may represent promising therapeutic candidates for the treatment of allergic asthma.
Highlights
Allergic asthma is one of the most common respiratory disorders and affects approximately 330 million people worldwide [1]
Recurrent and persistent asthma is driven by a T-helper 2 (Th2)-polarised immune response, eosinophilic inflammation, and airway remodelling, and it is characterised by subepithelial fibrosis and increased levels of collagen and other extracellular matrix (ECM) proteins [3]
Significant modulatory effects of AnxA1 occur through binding to formyl peptide receptors (FPRs), which are G-protein-coupled receptors (GPCRs), and studies have revealed that AnxA1 has a greater binding affinity to FPR2/ALX
Summary
Allergic asthma is one of the most common respiratory disorders and affects approximately 330 million people worldwide [1]. Studies have reported asthma prevalence rates, ranging between 1% and 18% in the general population of various countries [2]. Annexin (Anx)A1 is a 37 kDa glucocorticoid-induced protein that reproduces many of the pharmacological actions of glucocorticoids by binding to phospholipids in a Ca2+ -dependent manner, inhibiting cytosolic phospholipase A2 activity and preventing the synthesis of arachidonic acid-derived metabolites. This protein is widely distributed throughout the body and is constitutively produced by monocytes, macrophages, neutrophils, T cells [6,7,8], and mast cells [9]. Significant modulatory effects of AnxA1 occur through binding to formyl peptide receptors (FPRs), which are G-protein-coupled receptors (GPCRs), and studies have revealed that AnxA1 has a greater binding affinity to FPR2/ALX receptors [10]
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