There is increasing awareness of glycans participating in the communication of critical niche-cell and cell-cell information. A growing body of evidence implicates the ?2,6-sialylation of Gal(?1,4)GlcNAc termini, mediated by the sialyltransferase ST6Gal-1, as a central player in the regulation of diverse events including cell death, integrin-?1 function, stem cell maintenance, susceptibility to radio- and chemo-agents, myelopoiesis, and inflammation. Canonically, glycosylation is mediated by glycosyltransferases, including ST6Gal-1, residing within the ER-Golgi secretory apparatus of the same cells that produce them. However a significant pool of extracellular ST6Gal-1 exists, especially in the blood. Changes in the extrinsic ST6Gal-1 pool are associated with diverse pathologic conditions relating to stress and inflammation, and malignancies where elevated levels generally predict poorer patient outcomes. We observed that deficiency in circulating ST6Gal-1 results in an overly exuberant inflammatory response, which led to the overarching hypothesis that extracellular ST6Gal-1 remodels glycans on target immune cell surfaces, dampening response to inflammatory signals. Additional premise in support are: i) mature myeloid and marrow hematopoietic progenitor cells are targets of extrinsic ST6Gal-1 sialylation in vivo and in vitro; ii) extrinsic ST6Gal-1 suppresses G-CSF driven granulopoiesis; (iii) reduces M-CSF dependent generation of macrophages; (iv) decreases inflammatory cytokine expression and release by macrophage stimulated with LPS; and v) intravenous injection of recombinant ST6Gal-1 (rST6G) significantly ameliorates severe local and systemic inflammation in vivo. To acquire insight into this previously overlooked glycosylation mediated regulation of inflammation, three aims are proposed to examine i) which aspects of inflammatory cell biology are affected by extrinsic ST6Gal-1; ii) how does extrinsic ST6Gal-1 exert this action; and iii) what is the efficacy of rST6G in treating severe inflammation. The impact from the proposed work lies in the novelty of the previously overlooked extrinsic glycosylation axis, the ability of extrinsic ST6Gal-1 to suppress inflammation, and the innovation in the clinical potential of recombinant ST6Gal-1 to treat severe inflammatory conditions.
The circulating ST6Gal-1 mediates a novel extrinsic glycosylation pathway with striking anti-inflammatory properties that have significant potential as a clinical therapy. Severe inflammatory response syndrome (SIRS) is a major cause of mortality with currently limited treatment options, and survivors are frequently left with permanent injuries. This study will examine the mechanism of extrinsic ST6Gal-1 action and will test the ability of highly pure recombinant ST6Gal-1 in ameliorating severe inflammation in mouse models.
