Date: Tuesday, May 5, 2015
Session Name: Poster Session D: Innate Immunity in Transplantation
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Background: It has been shown that β-catenin is an important regulator of cell development, regeneration, and carcinogenesis. Our previous studies demonstrated the key role of β-catenin in the regulation of immune response at the innate-adaptive interface by controlling of dendritic cell (DC) programs in hepatic ischemia and reperfusion injury (IRI). However, it is unknown how β-catenin may affect macrophage-mediated innate immune response during the course of hepatic IRI. This study was designed to dissect the molecular mechanisms of β-catenin in regulating innate immunity in macrophages. Methods: The macrophage specific ablation of β-catenin (β-cateninM-KO) was generated by crossing β-catenin transgenic (β-cateninflox/flox) mice with LysM-Cre transgenic mice. Bone marrow-derived macrophages (BMMs) from β-cateninM-KO and β-cateninflox/flox mice were transfected with β-catenin-expressing vector (pB-β-catenin) or PPARγ siRNA/ROCK1 siRNA (100 nM), and then cultured for 24h followed by 6h of LPS (100 ng/ml) stimulation. Results: Myeloid-specific β-catenin deletion (β-cateninM-KO) in LPS-stimulated BMMs increased the expression of ROCK1, PTEN, and TLR4. However, transfection of pB-β-catenin in these cells decreased ROCK1 yet promoted PPARγ activation, increased p-Stat6 and PGC-1β expression. Disruption of PPARγ with siRNA in pB-β-catenin-transfected cells enhanced ROCK and PTEN activity. Moreover, ROCK1 siRNA knockdown in LPS-stimulated β-cateninM-KO cells diminished PTEN function leading to inhibiting TLR4/NF-κB activation, which accompanied by decreased expression of proinflammatory mediators. Conclusion: This study demonstrates that β-catenin regulates macrophage-mediated innate inflammatory responses by promoting PPARγ and depressing ROCK/PTEN activity, which in turn inhibits TLR4/NF-κB activation. Our novel findings underscore the crucial role of β-catenin in modulating PPARγ/ROCK/PTEN signaling within the innate immune system. Establishing macrophage β-catenin as a key regulator of innate immunity-mediated inflammation implies novel therapeutic potential for the management of liver IRI in transplant recipients.
To cite this abstract in AMA style:Yue S, Zhou X, Zhou M, Zhai Y, Busuttil R, Ying Q, Kupiec-Weglinski J, Ke B. Macrophage Specific β-Catenin Controls ROCK/PTEN Function and Regulates Innate Immunity in Liver Inflammation [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/macrophage-specific-catenin-controls-rockpten-function-and-regulates-innate-immunity-in-liver-inflammation/. Accessed December 2, 2020.
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