Macrophage Specific β-Catenin Controls ROCK/PTEN Function and Regulates Innate Immunity in Liver Inflammation
1Dumont-UCLA Transplant Center, Dept. of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
2Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Dept. of Stem Cell Biology & Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Meeting: 2015 American Transplant Congress
Abstract number: D82
Keywords: Inflammation, Ischemia, knockout, Liver
Session Information
Session Name: Poster Session D: Innate Immunity in Transplantation
Session Type: Poster Session
Date: Tuesday, May 5, 2015
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 October 9, 2024.« Back to 2015 American Transplant Congress