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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Hepatology 2016 ; 64 (5): 1683-98 Nephropedia Template TP
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THE MYELOID HSF1-?-CATENIN AXIS REGULATES NLRP3 INFLAMMASOME ACTIVATION IN MOUSE LIVER ISCHEMIA/REPERFUSION INJURY #MMPMID27474884
Yue S; Zhu J; Zhang M; Li C; Zhou X; Zhou M; Ke M; Busuttil RW; Ying QL; Kupiec-Weglinski JW; Xia Q; Ke B
Hepatology 2016[Nov]; 64 (5): 1683-98 PMID27474884show ga
Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. ?-catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1-?-catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia and reperfusion injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1-?-catenin signaling influenced the NLRP3-mediated innate immune response in vivo and in vitro. Using a mouse model of IR-induced liver inflammatory injury, we found that mice with a myeloid specific HSF1 knockout (HSF1M-KO) displayed exacerbated liver damage based on their increased serum ALT levels, intrahepatic macrophage/neutrophil trafficking, and pro-inflammatory IL-1? levels compared to the HSF1-proficient (HSF1FL/FL) controls. Disruption of myeloid HSF1 markedly increased transcription factor X-box-binding protein (XBP1), NLRP3 and cleaved caspase-1 expression, which was accompanied by reduced ?-catenin activity. Knockdown of XBP1 in HSF1-deficient livers using a XBP1 siRNA ameliorated hepatocellular functions and reduced the NLRP3/cleaved caspase-1 and IL-1? protein levels. In parallel in vitro studies, HSF1 overexpression increased ?-catenin (Ser552) phosphorylation and decreased reactive oxygen species (ROS) production in bone marrow-derived macrophages. However, myeloid HSF1 ablation inhibited ?-catenin but promoted XBP1. Furthermore, myeloid ?-catenin deletion increased XBP1 mRNA splicing, whereas a CRISPR/Cas9-mediated XBP1 knockout diminished NLRP3/caspase-1. Conclusions: The myeloid HSF1-?-catenin axis controlled NLRP3 activation by modulating the XBP1 signaling pathway. HSF1 activation promoted ?-catenin, which in turn inhibited XBP1, leading to NLRP3 inactivation and reduced IR-induced liver injury. Our findings demonstrated that HSF1-?-catenin signaling is a novel regulator of innate immunity in liver inflammatory injury and implied the therapeutic potential for the management of sterile liver inflammation in transplant recipients.
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Hepatology 2016 ; 64 (5): 1683-98
