Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Abstract

Background Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown. Objective The histological distribution, expression and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation. Methods Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by siglec blotting and isolation by siglec capture. Results Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, connective tissue); both were significantly upregulated in chronic rhinosinusitis patients. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B under inflammatory control via the NF-κB pathway, and mucin 5B carried sialoglycan ligands of Siglec-9 on human upper airway tissue. Conclusion Inflammation results in upregulation of immune inhibitory Siglec-8 and Siglec-9 sialoglycan ligands on human airways. Siglec-9 ligands were upregulated via the NF-κB pathway resulting in their enhanced expression on mucin 5B. Siglec sialoglycan ligand expression in inflamed cells and tissues may contribute to the control of airway inflammation.

Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8

“…Supporting this notion, an ex vivo study showed that eosinophils isolated from the brochoalveolar fluid of allergen-challenged patients have increased susceptibility to Siglec-8-mediated apoptosis (16). Immunohistochemical analysis consistently revealed that endogenous Siglec-8 ligands are markedly up-regulated in inflamed compared with normal human airway tissues (17). Collectively, these findings led to the proposal that Siglec-8 may provide a safeguard mechanism for the immune system to selectively deplete eosinophils from inflamed tissues and simultaneously diminish mast cell inflammatory responses and may thus constitute a basic immunoregulatory pathway to trigger the active resolution of inflammation and return to homeostasis (7,18) (Fig.…”

Targeting Neutrophils in Severe Asthma via Siglec-9

“…Similarly, human Siglec-9 ligands have been shown to participate in inflammation. In a study of patients with chronic rhinosinusitis, Jia et al [74] demonstrated that Siglec-9 ligands were significantly upregulated in a subset of submucosal gland cells, epithelium, and connective tissue of the inferior turbinate. Upregulation of Siglec-9 ligands could, in turn, elevate the expression of mucin 5B in an NF-κB-dependent pathway.…”

Siglec-E Negatively Regulates the Activation of TLR4 by Controlling Its Endocytosis

“…Siglecs predominantly bind to sialic acids on cell surface proteins (17), and play an important role in the internalization of sialic acid-expressing pathogens (18–20), in controlling allergic asthma (21, 22), and in self-tolerance (23). Previously, we found that interaction between CD24 and SiglecG/10 is a key regulator of polybacterial sepsis, and this interaction requires sialylation of CD24 (24, 25).…”