Siglec-F and Resolution of Allergic Inflammation

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Abstract While much is known about the induction of the inflammatory response in allergic inflammation, far less is understood about endogenous mechanisms that naturally down- regulate allergic inflammatory responses. These endogenous responses could potentially be harnessed to develop novel anti-inflammatory therapies for hypersensitivity diseases. In this proposal we propose to investigate the role that activation of Siglec-F (Sialic acid-binding Ig-superfamily lectin-F) cell surface receptors play in down-regulating the inflammatory, and tissue remodeling response in allergic inflammation. Siglec-F is highly expressed on cells associated with allergic inflammation such as eosinophils. A functional role for Siglec-F receptors in regulating allergic responses is suggested from the presence in their cytoplasmic tails of ITIM motifs know to be involved in inhibitory signaling pathways in the immune system. We therefore propose to determine 1) the mechanisms by which Siglec-F exerts this anti-allergic effect in vivo and in vitro, and 2) identify and characterize ligands specific for Siglec-F that may be generated by epithelium during an allergic inflammatory response in vivo, (as their name implies Siglecs bind to ligands expressing the glycan sialic acid), and 3) characterize the expression of Siglec-8 (the human orthologue of mouse Siglec-F) and its ligand at sites of eosinophilic inflammation in humans with asthma.