Sialic acid-binding immunoglobulin-like lectin 9 as a potential therapeutic target for chronic obstructive pulmonary disease / 中华医学杂志(英文版)

Chronic obstructive pulmonary disease (COPD) has become the third-leading cause of death worldwide, which is a severe economic burden to the healthcare system. Chronic bronchitis is the most common condition that contributes to COPD, both locally and systemically. Neutrophilic inflammation predominates in the COPD airway wall and lumen. Logically, repression of neutrophilia is an essential fashion to COPD treatment. However, currently available anti-neutrophilic therapies provide little benefit in COPD patients and may have serious side effects. Thus, there is an urgent need to explore an effective and safe anti-neutrophilic approach that might delay progression of the disease. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9 is a member of the Siglec cell surface immunoglobulin family. It is noteworthy that Siglec-9 is highly expressed on human neutrophils and monocytes. Ligation of Siglec-9 by chemical compounds or synthetic ligands induced apoptosis and autophagic-like cell death in human neutrophils. Furthermore, administration of antibody to Siglec-E, mouse functional ortholog of Siglec-9, restrained recruitment and activation of neutrophils in mouse models of airway inflammation in vivo. Given the critical role that neutrophils play in chronic bronchitis and emphysema, targeting Siglec-9 could be beneficial for the treatment of COPD, asthma, fibrosis, and related chronic inflammatory lung diseases.

Effect of Anti-Siglec-F Antibody and Reactive Oxygen Species Blocking on Histamine Release in Urinary Bladder of Ovalbumin-Treated Mice / 대한배뇨장애요실금학회지

PURPOSE: Sialic acid-binding Ig-like lectin (Siglec) is an immune inhibitory receptor that plays a role in the negative regulation of the activation of immune cells. This study aimed to evaluate the effects of anti-Siglec-F on plasma and urinary histamine levels in ovalbumin (OVA)-challenged urinary bladder in mice. METHODS: Thirty BALB/c mice were used. In group I (control group, n=5), mice were sensitized with OVA and challenged with saline. In group II (OVA challenge group, n=5), OVA was used for intraperitoneal sensitization and intravesical challenge. The challenged mice in group III (control immunoglobulin G [IgG] group, n=5) and those in group IV (anti-Siglec-F group, n=5) were intraperitoneally pretreated with rabbit control IgG or anti-Siglec-F antibody, respectively. In groups V (N-acetylcysteine [NAC] in OVA challenge group, n=5) and VI (control NAC only, n=5), mice were pretreated with NAC. RESULTS: Urinary histamine concentrations were significantly higher 7 days after intravesical OVA challenge (P<0.01), whereas plasma histamine levels were not. Pretreatment with anti-Siglec-F antibody significantly prevented the increase in urinary histamine release (P<0.05), whereas pretreatment with the IgG antibody control did not. Also, pretreatment of the OVA challenge group with NAC did not affect the histamine concentration in either urine or plasma. CONCLUSIONS: Systemic anti-Siglec-F treatment showed anti-allergic effects at least on local histamine release, particularly in the lower urinary bladder.

Specific regulator of eosinophil apoptosis: Siglec-8-new hope for bronchial asthma treatment / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>It is known that Siglec-8 is selectively expressed on human eosinophils at a high level and mediates eosinophil apoptosis when crosslinked with its antibody. The aim of our review is to elucidate the molecular and biological characteristic of Siglec-8 and then discuss the function and possible mechanisms of Siglec-8 in eosinophils. Thereby, we will expand our understanding to the regulation of eosinophil apoptosis, and provide important clues to the treatment of asthma and other hyper-eosinophilic diseases.</p><p><b>DATA SOURCES</b>Most articles were identified by searching of PubMed online resources using the key term Siglecs.</p><p><b>STUDY SELECTION</b>Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected.</p><p><b>RESULTS</b>Siglec-8 is selectively expressed on human eosinophil and can specifically induce eosinophil apoptosis.</p><p><b>CONCLUSION</b>The restricted expression of Siglec-8 on human eosinophil and the rapid progress in understanding its role as cell signaling and activation of death receptors have made it an attractive target for treatment of asthma and other hyper-eosinophilic diseases.</p>

New Insights into the Mechanism of the Down-Regulation of Mast Cells in the Treatment of Interstitial Cystitis: Possible Role of Siglecs / 대한배뇨장애요실금학회지

No abstract available.

Potential Targeting of Siglecs, Mast Cell Inhibitory Receptors, in Interstitial Cystitis / 대한배뇨장애요실금학회지

Mast cell increases and activation are detected in the chronic inflammatory bladder disease interstitial cystitis (IC), and their proinflammatory mediators are felt to contribute to regional pelvic pain and inflammatory pathophysiology. The immunoreceptor tyrosine-based inhibition motif-containing sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed in mast cells could be evaluated as in vivo signaling regulators capable of inhibiting IC-related mast cell activation.

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

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.

Functions of Siglecs in Allergic Inflammation / 소아알레르기및호흡기학회지

Siglecs are sialic acid binding Ig-like lectins, subset of the immunoglobulin superfamily. They are characterized by a homologous N-terminal V-set Ig-like domain and C2 set Ig-like domains. N-terminal domains have sialic acid binding activity. In humans, 11 Siglecs have been described sialoadhesin(Siglec-1), CD22(Siglec-2), CD33(Siglec-3), MAG(Siglec-4), more recently described CD33-related Siglecs(Siglec 5-11). Siglecs express most signal via immunoreceptor tyrosine-based inhibition motif(ITIM) cytoplasmic domains. The cytoplasmic tails of all Siglecs except sialoadhesin have one or more tyrosine residues within potential signaling motifs. Inhibitory function of other Siglecs such as Siglec-7 or Siglec-9 was shown in RBL-2H3 cells. Co-crosslinking of Siglec-7 or Siglec-9 and Fc epsilon R1 substantially reduced the serotonin release of RBL-7 and RBL-9 cells. Siglec-8 is expressed on human eosinophils, mast cells and basophils. Siglec-8 has two tyrosine motifs, a proximal motif and a distal motif. They have some inhibitory functions in immune system. We have observed that Siglec-8 is able to inhibit the IgE receptor-mediated beta-hexosaminidase release of RBL-2H3 cells following co-crosslinking. Co-crosslinking of Siglec-8 and Fc epsilon R1 reduced the hexosaminidase release of RBL-2H3 cells. These results show that Siglec-8 is as potent as Siglec-7 and Siglec-9 in delivering inhibitory signals to RBL-2H3 cells. Siglec-8 should be a new member of the inhibitory receptor superfamily and the membrane-proximal ITIM is essential for the inhibitory function of Siglec-8 molecules. Although these molecules present specific marker for the allergic cell types, more work is needed to understand the signaling mechanism and the role in various disease processes.