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 chronic. Chronic inflammation is considered the underlying cause of many
diseases of the modern world, such as arthritis, asthma, and many others, and much effort has gone into trying
to block the development of inflammation. However, these approaches also increase the risk of serious
infection due to simultaneous inhibition of host defense against microbial pathogens. Recent work has
demonstrated that resolution of inflammation is an active process. Thus, therapeutics may be developed
capable of inducing resolution of chronic inflammatory disease. The clearance of apoptotic cells (AC) from the
inflammatory site has been identified as a key component of the resolution process. The uptake of AC by
inflammatory macrophages (efferocytosis) induces their down-regulation of pro-inflammatory cytokines and up-
regulation of anti-inflammatory mediators, increases efferocytosis, inhibits further neutrophil recruitment, and
promotes tissue healing and homeostasis. In addition, the clearance of AC also prevents their undergoing
secondary necrosis, leaking cytosolic contents and prolonging inflammation. Thus, a more complete
understanding how efferocytosis modulates macrophages from pro-inflammatory to pro-resolution is needed.
Eicosanoids are powerful lipid mediators derived from the metabolism of arachidonic acid. They mediate many
aspects of the inflammatory response and play important roles in resolution. Omega-3 fatty acid metabolism
produces a class of lipids called specific pro-resolving mediators (SPM) capable of inducing resolution of
inflammation. My lab is interested in defining the mechanisms used by eicosanoids and SPM to induce the
resolution of inflammatory disease. We use a mouse model of Lyme arthritis caused by infection of C3H mice
with the spirochete, B. burgdorferi. This proposal has two specific aims: Aim 1 will explore the mechanism of
how AC engulfment by inflammatory macrophages alters their function. We will determine the roles of various
eicosanoid metabolic pathways (COX, 5-LOX and 12/15-LOX) and SPM in these responses. Aim 2 will explore
the enhanced effect of activated AC (previous exposure to bacteria) on arthritis resolution, and the roles of
eicosanoids and SPM in this process. Successful completion of these aims will lay the groundwork for further
studies to elucidate the regulatory mechanisms of how, during an infectious inflammatory response, the system
switches from pro-inflammatory to pro-resolution and the impact infectious agents have on this decision. These
studies will broaden our understanding of inflammatory disease and may impact our ability to lessen chronic
inflammation while sparing host defense.