Siglec-8: Novel Therapeutic Approach for Eosinophilic Inflammation and Airway Remodeling

Song, Dae Jin

Abstract

Eosinophil is an important therapeutic target in the management of asthma due to their important role in airway inflammation, induction of airway hyperresponsiveness and their recently described role in airway remodeling. One such strategy targeting eosinophils is to target receptors expressed by eosinophils that might mediate the resolution of eosinophilic inflammation. One candidate receptor expressed by eosinophils is Siglec-8. Siglec-8 belongs to the CD33-related Siglec (CD33rSiglec) family, which are a subclass of Siglecs defined by their mutual sequence similarity (share about 50-80% sequence similarity), and clustered gene localization (chromosome 19q in humans). The cytoplasmic domain of the Siglec-8 contains immunoreceptor tyrosine-based inhibition motifs (ITIMs), suggesting that this molecule possesses inhibitory functions. In vitro studies demonstrated that cross-linking Siglec-8 receptors on eosinophils induced an apoptotic signal through the sequential production of reactive oxygen species (ROS), followed by induction of mitochondrial injury and caspase cleavage. In vivo studies using Siglec-F (functional paralog of Siglec-8) deficient mice demonstrated that Siglec-F deficient mice challenged with inhaled allergen significantly enhanced levels of eosinophilic airway inflammation as well as delayed resolution of eosinophilic inflammation. Administration of an anti-Siglec-F antibody significantly reduced levels of allergen induced eosinophilic airway inflammation and features of airway remodeling by reducing the production and increasing the clearance of eosinophils in murine model of asthma. Although further studies are needed to elucidate the precise role of Siglec-8, the results of these studies suggest that targeting of Siglec-8 may be a novel therapeutic approach for asthma and other allergic disease.