The immune system consists of billions of specialized cells in constant motion that function to maintain homeostasis within the human body. Among them, monocytes are a population of circulating mononuclear cells that can cross the vascular endothelium and move into sites if inflammation, where they participate in the clearance of pathogens and the repairing of damaged tissue. The ability of certain monocytes to express components of the extracellular matrix defines them as fibrocytes. This cell population has recently come under intense scrutiny due to their pathological contribution to chronic inflammation and fibrosis in a variety of organs, including the cornea. Critical to the functions of the immune cells is the glycocalyx, a diverse mixture of glycans that functions as the primary interface with the environment. Glycans play a vital role in both the innate and adaptive immune systems by regulating signaling pathways and the activation of multiple cell types. The Lewis blood group antigens are among the most important cell surface glycan determinants in immunology, as they promote interaction with cell adhesion molecules expressed on the surface of endothelial cells. Because of its significance to the immune reponse, there has been a need for the past few years to define how the glycome of immune cells is regulated. It has become increasingly clear that galectins play a critical role as modulators of the immune response. They can interact with cell surface receptors to promote cell differentiation, affect cell growth and survival, and modulate cell adhesion. We hypothesize that galectins play a dynamic role in the regulation of the immune response by directing the immune cell glycome. The following specific aims will address this objective: (1) to determine whether galectins influence the glycome of human mononuclear cells, (2) to investigate the role of galectin-3 as a functional regulator of the sialyl Lewis X antigen in activated monocytes, and (3) to investigate the role of galectin-3-dependent glycosylation in the trafficking and accumulation of corneal fibrocytes. It is anticipated that this research will have significant translational impact given the impact of circulating fibrocytes to wound healing and scar formation.
Nowhere is the biological function of the glycocalyx more evident than in the immune system, where it contributes to orchestrate the inflammatory response. In this application, we propose to determine the role of galectins in the regulation of the inflammatory response by directing the composition of the immune cell glycocalyx. In doing so, we anticipate uncovering a novel regulatory mechanism for immune cell migration into the cornea that might have therapeutic consequences.
