Receptor Cd74 integrates meta-inflammation in alcohol-associated liver disease - PROJECT SUMMARY The role of inflammation in alcohol-associated liver disease has been thoroughly researched over the past few decades. Despite this intensive focus on ALD pathophysiology, we have yet to realize meaningful improvements to therapeutic design in humans. Our laboratory has established that macrophage migration inhibitory factor (MIF) is a dynamic and multifaceted contributor to ALD. Furthermore, as our data will show, specific depots of MIF, like hepatocytes and myeloid cells, contribute to ALD pathophysiology through distinct mechanisms. The crosstalk between MIF and its cognate receptor, CD74, within the resident liver populations and infiltrating cells from the periphery in ALD is not yet known. The overall goal for this proposal is to define the contributions of MIF-CD74 signaling in ALD. Our preliminary data show that although hepatocyte- and myeloid-derived Mif deficiency protected from ethanol-mediated steatosis, inflammation and cell death in the liver, the hepatic transcriptomic program was divergent in these models despite equivalent protection from injury. Interestingly, expression of Mif is robust in the hepatocyte compartment, but Cd74 is largely confined to the monocytes/macrophages in a quiescent liver, but its expression is increased by ethanol, possibly due to immune cell accumulation or upregulation of expression in hepatocytes. This suggests that the role of Cd74 in ethanol feeding and ALD might be augmented throughout the progression of the disease and we will target expression of Cd74 by multiple means in models of ethanol feeding. Moreover, the role of MIF in fibrosis remains controversial, with several publications describing both protective and deleterious roles of MIF-CD74 signaling, but were limited to use of global knockouts. Our unique animal models and experience in ethanol feeding will allow us to scrutinize the Mif-Cd74 pathway in multiple cellular depots in models of fibrosis. The proposed research plan over the funding period will be divided into three specific aims that will 1) define and characterize the role of Cd74 expression in hepatocytes and myeloid compartments during and after ethanol feeding models in mice, 2) resolve the controversy of the role of MIF-CD74 pathway in hepatic fibrosis, and 3) therapeutic targeting of hepatic MIF and CD74 via anti-sense oligonucleotide technology. These proposed areas will have profound implications in innate immune responses in ALD, and will support scrutinizing the distinctive, tissue-specific expression of mediators of tissue injury in chronic diseases of the liver.
