"The Role of Syndecan-1 in the Resolution of Chronic Inflammatory Responses"

Advisor: Elliot L. Chaikof, M.D. Ph.D. (Georgia Institute of Technology, Harvard Medical School, Beth Israel Deaconess Center )

Committee:
Julia E. Babensee, Ph.D. (Georgia Institute of Technology)
J. Brandon Dixon, Ph.D. (Georgia Institute of Technology)
Carolyn Haller, Ph.D. (Harvard Medical School, Beth Israel Deaconess Center)
Larry V. McIntire, Ph.D. (Georgia Institute of Technology)
W. Robert Taylor, M.D., Ph.D. (Georgia Institute of Technology, Emory University)

Resolution of acute inflammation is a tightly regulated host response that is essential in ensuring tissue healing and complete return to homeostasis.  Traditionally regarded as a passive process, recent studies indicate that resolution of inflammation is an active process that involves activation of specific host responses.  It is speculated that the expression of Syndecan-1 (Sdc-1), which is a member of a family of cell surface proteoglycans that can bind and modulate the activity of a diverse group of ligands, is part of the activated host response to tissue injury that contributes to the resolution of inflammation.  The objective of this work is to understand how Sdc-1 plays a critical part in an anti-atherogenic program necessary for the clearance of monocyte-derived cells out of the inflamed vascular wall by emigration and/or efferocytosis, promoting the resolution of inflammation.  
During the course of this research, we demonstrated that Sdc-1 expression on macrophages is associated with an anti-inflammatory, pro resolution polarization state and enhanced migration.  Macrophage Sdc-1 expression was also found to be correlated with CXCR4 expression, both of which can be upregulated in response to efferocytosis.  Importantly, both macrophage Sdc-1 and CXCR4 was found to participate in the regulation of macrophage egress from the inflammation site to the draining lymphatics during the resolution of inflammatory response.  While the overall mechanisms regulating resolution processes are unknown, our work has managed to identify two components that are involved in the process: macrophage Sdc-1 and macrophage CXCR4 expression.  Collectively, these results reinforce the physiological significance of macrophage efferocytosis and macrophage motility as endogenous modulators of the inflammatory response.