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American Liver Foundation
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New York, New York 10006
American Liver Foundation Postdoctoral Research Fellowship Award
University of California, San Diego, San Diego, California
“Regulation of liver macrophages in liver fibrogenesis”
Liver fibrosis is a common consequence of chronic liver injury, which progresses to cirrhosis. Liver macrophages including Kupffer cells are important for inducing inflammation and activation of hepatic stellate cells (HSCs), major producer of extracellular matrix proteins including collagen, in the development of liver fibrosis. Previous studies suggested that liver macrophages have two particular properties, inflammation inducing macrophages (M1 type) and inflammation preventing macrophages (M2 type). Few studies have examined on anti-inflammatory macrophages in liver disease. Dr. Aoyama hypothesizes that anti-inflammatory macrophages are crucial for regulating liver inflammation and fibrosis. Thus, he will investigate the role of anti-inflammatory macrophages in liver inflammation and fibrosis by focusing on chemokine receptor CX3CR1, a CX3CL1 (Fractalkine) ligand, and TAK1, an intracellular signaling molecule activated by TLR, TNF receptor, IL-1 receptor and TGF-b receptor signaling. He will use CX3CR1-/- mice and macrophage specific TAK1-/- mice (TAK1DMac) generated by crossing TAK1 flox/flox mice with CD11b Cre transgenic mice. Liver fibrosis will be induced by chronic carbon tetrachloride (CCl4) injection. Primary liver macrophages and stellate cells will be isolated from these mice for in vitro cell culture experiments. For CX3CR1 study (Aim 1), Dr. Aoyama will examine liver inflammation and fibrosis in CX3CR1-/- mice following chronic CCl4 treatment. Then, he will isolate liver macrophages from CX3CR1-/- and WT mice to characterize their phenotype. Cells will also be stimulated with recombinant CX3CL1 to test whether the phenotype of liver macrophages will be changed. Lastly, he will test if CX3CL1 treatment prevents liver fibrosis. His preliminary data has already shown that CX3CR1-/- mice show increased liver inflammation and fibrosis after chronic CCl4 treatment, suggesting that some liver macrophages negatively regulate liver inflammation and fibrosis through CX3CR1. He anticipates that CX3CL1-CX3CR1 interaction is crucial for regulating inflammatory phenotypes in macrophages during liver inflammation and fibrosis. For TAK1 study (Aim 2), he will examine liver inflammation and fibrosis in TAK1DMac mice. Primary liver macrophages will be also examined for assessing TAK1-mediated intracellular signaling and cytokine production. In general, TAK1 is required for TLR signaling to promote inflammatory responses. Contrary to general expectation, his preliminary data clearly demonstrated that TAK1DMac mice show increased liver inflammation and fibrosis. He anticipates that TAK1 is a negative regulator in liver macrophages, which has not been identified yet. Dr. Aoyama’s study will identify this uncovered signaling mechanism mediated by TAK1 in liver macrophages. This study will provide a novel insight into some particular macrophages that are anti-inflammatory and anti-fibrotic. Anti-inflammatory type of macrophages, besides inflammatory macrophages, is crucial for regulating the development of liver inflammation and fibrosis.