Abstract
BackgroundIn this study we examined the role of Siglec-F, a receptor highly expressed on eosinophils, in contributing to mucus expression, airway remodeling, and Siglec-F ligand expression utilizing Siglec-F deficient mice exposed to chronic allergen challenge.MethodsWild type (WT) and Siglec-F deficient mice were sensitized and challenged chronically with OVA for one month. Levels of airway inflammation (eosinophils), Siglec-F ligand expresion and remodeling (mucus, fibrosis, smooth muscle thickness, extracellular matrix protein deposition) were assessed in lung sections by image analysis and immunohistology. Airway hyperreactivity to methacholine was assessed in intubated and ventilated mice.ResultsSiglec-F deficient mice challenged with OVA for one month had significantly increased numbers of BAL and peribronchial eosinophils compared to WT mice which was associated with a significant increase in mucus expression as assessed by the number of periodic acid Schiff positive airway epithelial cells. In addition, OVA challenged Siglec-F deficient mice had significantly increased levels of peribronchial fibrosis (total lung collagen, area of peribronchial trichrome staining), as well as increased numbers of peribronchial TGF-β1+ cells, and increased levels of expression of the extracellular matrix protein fibronectin compared to OVA challenged WT mice. Lung sections immunostained with a Siglec-Fc to detect Siglec-F ligand expression demonstrated higher levels of expression of the Siglec-F ligand in the peribronchial region in OVA challenged Siglec-F deficient mice compared to WT mice. WT and Siglec-F deficient mice challenged intranasally with IL-4 or IL-13 had significantly increased levels of airway epithelial Siglec-F ligand expression, whereas this was not observed in WT or Siglec-F deficient mice challenged with TNF-α. There was a significant increase in the thickness of the peribronchial smooth muscle layer in OVA challenged Siglec-F deficient mice, but this was not associated with significant increased airway hyperreactivity compared to WT mice.ConclusionsOverall, this study demonstrates an important role for Siglec-F in modulating levels of chronic eosinophilic airway inflammation, peribronchial fibrosis, thickness of the smooth muscle layer, mucus expression, fibronectin, and levels of peribronchial Siglec-F ligands suggesting that Siglec-F may normally function to limit levels of chronic eosinophilic inflammation and remodeling. In addition, IL-4 and IL-13 are important regulators of Siglec-F ligand expression by airway epithelium.
Highlights
In this study we examined the role of Siglec-F, a receptor highly expressed on eosinophils, in contributing to mucus expression, airway remodeling, and Siglec-F ligand expression utilizing Siglec-F deficient mice exposed to chronic allergen challenge
As in previous studies we have demonstrated that Wild type (WT) mice challenged with allergen have increased levels of expression of Siglec-F ligands in the airway epithelium and peribronchial cells [3,5], we examined whether the absence of Siglec-F receptors in Siglec-F deficient mice would modulate levels of SiglecF ligands expressed in the airway of Siglec-F deficient compared to WT mice
Chronic OVA challenged Siglec-F deficient mice have increased levels of bronchoalveolar lavage (BAL) eosinophils and peribronchial eosinophils Chronic OVA challenge in WT mice induced a significant increase in the number of BAL eosinophils (p < 0.0001)(WT OVA vs WT no OVA)(Figure 1A), as well as a significant increase in the number of peribronchial eosinophils (p < 0.0001)(WT OVA vs WT no OVA)(Figure 1B) compared to non-OVA challenged mice
Summary
In this study we examined the role of Siglec-F, a receptor highly expressed on eosinophils, in contributing to mucus expression, airway remodeling, and Siglec-F ligand expression utilizing Siglec-F deficient mice exposed to chronic allergen challenge. Siglec-F (Sialic acid-binding Ig-superfamily lectin-F) belongs to the CD33-related Siglec (CD33rSiglec) family which are a subclass of Siglecs defined by their mutual sequence similarity and clustered gene localization (chromosome 7 in mouse; chromosome 19q in humans) [1]. Most of the CD33rSiglecs are expressed on cells involved in innate immunity, such as monocytes, granulocytes, macrophages and natural killer cells [1]. Siglec-F is a transmembrane receptor comprising a ligand binding V-set domain, three C-2 domains, a transmembrane domain, and a cytoplasmic ITIM motif (immunoreceptor tyrosine-based inhibitory motif), which is known to be involved in inhibitory signaling pathways in the immune system [9,10]. Support for inhibitory signaling by the cytoplasmic domain of CD33rSiglecs have come from studies which have demonstrated that antibody cross-linking of several CD33rSiglecs results in inhibition of cellular-activation signals, arrest of proliferation, or induction of apoptosis [11,12,13]
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