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.
During inflammation, the clearance of dead cells by macrophages signals them to switch from driving the inflammation to driving resolution and healing. Bioactive lipids play an important role in mediating this switch, but the mechanisms are not clear. We propose to use cell culture experiments and a mouse model of Lyme arthritis to define these mechanisms.
