Sentinels of Homeostasis: Lipid Mediators in Immune Regulation and Neuroprotection

Lipid mediators are fatty acid-derived small signaling molecules that are critical in vascular responses and leukocyte trafficking during inflammation. Eicosanoids prostaglandin E2 (PGE2) induces pain and fever responses while leukotriene B4 (LTB4) recruits neutrophils to initiate inflammation, the recruited neutrophils subsequently produce lipoxin A4 (LXA4) to limit the magnitude and duration of acute inflammation. Eicosanoid regulation of innate immune cells is well established, but eicosanoid regulation of adaptive immunity is less understood. Moreover, the bioactions of eicosanoids are often context-dependent. Therefore to fully understand how lipid mediators modulate immune responses and homeostasis, it is vital to assess their immunological mechanisms in cell type- and disease-specific settings./nMy dissertation aims to address whether and how LXA4 mediates adaptive immune responses in posterior autoimmune uveitis. In the first Chapter I will introduce arachidonic acid-derived eicosanoids PGE2, LTB4, LXA4 and lipoxin B4 (LXB4) and discuss their multifaceted bioactions in various inflammatory settings, with the focus of their regulation of lymphocytes. In Chapter Two I will provide an overview on the therapeutic effects of special proresolving mediators (SPMs) and LXA4 in ocular diseases and briefly highlight two collaborations that revealed the roles of PGE2 and LTB4 in enhancing inflammatory neutrophil function in peritonitis, and the mechanism in which PGE2 contributes to pruritic responses in atopic dermatitis./nChapter Three will present my thesis aims in identifying whether LXA4 plays a role during autoimmune uveitis pathogenesis and dissecting the mechanism in which LXA4 modulates disease. Data from my thesis project showed in vivo generation of LXA4 was significantly downregulated in the draining lymph nodes at peak uveitis. Mice lacking 5-lipoxygenase (5-LOX), the rate-limiting enzyme for LXA4 production, exhibited aggravated disease. Ccr7 expression was downregulated in CD4+ T cells of LXA4 deficient mice while glycolytic responses of these T cells were enhanced, resulting in elevated IFN- production and migration of effector CD4+ T cells to the eye. Conversely, LXA4 treatment of immunized mice ameliorated disease. The findings underscore the importance of the LXA4 circuit in guiding adaptive T cell function in autoimmunity, and uncover a novel mechanism of LXA4 regulation in T cell effector function and trafficking from peripheral lymph nodes to the site of inflammation./nChapter Four demonstrates a novel neuroprotective role of astrocyte-secreted lipoxins A4 and B4 in retinal neurodegeneration. Lipoxins’ anti-inflammatory functions are well established, but they have not been shown to impact neuronal survival. In this project, we determined that LXA4 and LXB4 are synthesized in the inner retina in health, but their endogenous formation becomes reduced following injury. Lipoxin treatment provided neuroprotection following acute injury, while inhibition of the LXA4 pathway exacerbated injury-induced neuronal death. These results identified lipoxins as important neuroprotective factors that maintain neuronal homeostasis and inflammation in the central nervous system (CNS)./nIn the last chapter, I will conclude with the main findings from my projects and suggestions for future studies on lipid mediators. In this dissertation, we demonstrate the indispensable roles of lipoxins in maintaining homeostasis and mediating inflammatory responses, and their abilities in fine-tuning cellular responses to control the duration and amplitude of inflammation.

Advisor: Gronert, Karsten