The Impact of Tissue Sialylation on Macrophage Polarization and Function

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Summary Tissue-resident macrophages play important roles in maintain tissue homeostasis. They broadly fall into two categories: classically-activated and pro-inflammatory macrophages (M1) and alternatively-activated and anti- inflammatory macrophages (M2). Within immune privileged tissues, such as the lung and liver, macrophages, such as liver Kupffer cells, are typically described as M2. Our preliminary data suggests that the M2 phenotype in the liver depends at least in part upon the glycome of the surrounding parenchyma, particularly the hepatocytes. We have found that α2,6-linked sialic acids upon hepatocyte surface glycans promotes normal M2 polarization, but that loss of this sialylation drives M1 polarization and subsequent aberrant T cell activation which leads to increased inflammatory disease susceptibility. In this proposal, we seek to determine the mechanism by which α2,6-sialylated glycans in the liver drives changes in resident macrophage phenotype and T cell activation. The proposed studies are broken into three aims, with the first two focused upon the influence of α2,6-sialylated glycans on macrophage function and signaling, and the third focused upon the mechanism underlying increased T cell activation and disease in the absence of sialylation. We believe that these studies will introduce a novel immune checkpoint receptor which binds sialylated glycans, inhibits signal transduction, promotes M2 polarization, and leads to immune homeostasis.