Mechanisms of Reverse Transendothelial Migration in Arthritis Resolution

3. Abstract Inflammation is a beneficial response to infection or tissue damage and mediates the removal of microbial pathogens and restoration of the tissue to homeostasis. Occasionally the inflammatory response does not resolve properly and becomes a chronic process, resulting in diseases such as arthritis, asthma, and many others. Significant effort has gone into developing therapeutics to block

the development of inflammation; however, these approaches also increase the risk of serious infection due to simultaneous inhibition of the host immune defense against microbial pathogens. Recent work has demonstrated that the resolution of inflammation is an active and dynamic process. Neutrophils recruited to the infected/damaged tissue phagocytose and kill invading bacteria, undergo

apoptosis, and are cleared by macrophages (efferocytosis). Efferocytosis is a key component of the resolution process and induces a switch from pro-inflammatory to anti-inflammatory processes in macrophages. This switch results in decreased pro-inflammatory cytokine production, increased production of anti-inflammatory mediators, enhanced efferocytosis, diminished neutrophil recruitment,

and promotes tissue healing and a return to homeostasis. Recently, however, another mechanism has been described that may directly impact inflammation resolution, reverse transendothelial migration of neutrophils (rTEM). In this mechanism, neutrophils that enter the tissue during inflammatory responses do not die there, but rather re-enter the vasculature and travel to the lungs

before proceeding to the bone marrow where they ultimately die. This process appears to be at least partially mediated by eicosanoids, specifically LTB4, PGE2, and LXA4. Our previous work has demonstrated the failure of Lyme arthritis resolution in mice deficient in these inflammatory mediators. Based upon our preliminary data, we hypothesize that neutrophils that enter tissues and encounter

microbes will remain in the tissues and undergo apoptosis there, if there are no microbes encountered the neutrophils will undergo rTEM and exit the tissue. This proposal will investigate the role of rTEM in inflammation resolution and the roles of LTB4, PGE2, and LXA4 in mediating this response. Successful completion of these studies will provide new knowledge and understanding of

neutrophil trafficking during inflammation and the role of rTEM in inflammation resolution.