Siglec-mediated regulation of neutrophil during sepsis

Abstract

Neutrophils are critical for controlling bacterial infections. Neutrophil activation, recruitment, and killing of bacteria are the key events involved in controlling the infection. These events are guided by activatory receptors expressed on neutrophils that respond to the bacterial infection. Emerging data suggests that overstimulation of these activatory receptors impairs neutrophil migration to sites of infection, leading to spread of pathogenic bacteria that can give rise to septic shock. Given the lack of treatment strategies for sepsis, there is a great need for understanding how these activatory receptors are regulated. Inhibitory receptors play important roles in fine-tuning activatory receptors and are of therapeutic interest because dampening activatory receptors is predicted to improve neutrophil migration to sites of infection. Inhibiting neutrophil function in distal organs - where neutrophil-induced tissue injury drives septic shock – is also of high therapeutic interest. Inhibitory receptors on neutrophils include members of the Siglec family that have strong immunomodulatory properties through their ability to recruit phosphatases to dampen cellular signaling. Indeed, a growing number of studies have shown that Siglec-5 and -9 on human neutrophils modulate neutrophil responses. A major outstanding question is which activatory receptors on human neutrophils are being regulated by the individual Siglecs, which is difficult to access using conventional approaches. In this proposal, we will develop a biochemical approach involving liposomal nanoparticles that co-display activatory ligands and selective glycan ligands targeting the Siglecs, to systematically address what classes of activatory receptors on human neutrophils can be inhibited by Siglecs. We wil further establish how Siglec function is altered during sepsis and the potential of exploiting Siglecs to dampen inhibitory receptors on neutrophils as a therapeutic strategy. Through synergy developed in this FAPESP-SCRIPPS collaboration, important insights into neutrophil function will be made, which will be of high therapeutic interest from a standpoint of a strategy for treating sepsis. (AU)