The myeloid heat shock transcription factor 1/β‐catenin axis regulates NLR family, pyrin domain‐containing 3 inflammasome activation in mouse liver ischemia/reperfusion injury. Issue 5 (29th August 2016)

• Record Type: Journal Article
• Authors: Yue, Shi; Zhu, Jianjun; Zhang, Ming; Li, Changyong; Zhou, Xingliang; Zhou, Min; Ke, Michael; Busuttil, Ronald W.; Ying, Qi‐Long; Kupiec‐Weglinski, Jerzy W.; Xia, Qiang; Ke, Bibo
• Is Part Of: Hepatology. Volume 64:Issue 5(2016:Nov.)
• Page Start: 1683
• Page End: 1698
• Publication Date: 2016-08-29
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.28739
• Languages: English
• ISSNs: 0270-9139

Abstract

Abstract : Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. β‐catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1‐β‐catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia/reperfusion (I/R) injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1‐β‐catenin signaling influenced 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 (HSF1 M‐KO ) displayed exacerbated liver damage based on their increased serum alanine aminotransferase levels, intrahepatic macrophage/neutrophil trafficking, and proinflammatory interleukin (IL)‐1β levels compared to the HSF1‐proficient (HSF1 FL/FL ) controls. Disruption of myeloid HSF1 markedly increased transcription factor X‐box‐binding protein (XBP1), NLR family, pyrin domain‐containing 3 (NLRP3), and cleaved caspase‐1 expression, which was accompanied by reduced β‐catenin activity. Knockdown of XBP1 in HSF1‐deficient livers using a XBP1 small interfering RNA ameliorated hepatocellular functions and reduced NLRP3/cleaved caspase‐1 and IL‐1β protein levels. In parallel in vitro studies, HSF1 overexpression increased β‐catenin (Ser552) phosphorylation and decreased reactive oxygen species (ROS) production in bone‐marrow‐derived macrophages. However, myeloid HSF1 ablation inhibited β‐catenin, but promoted XBP1. Furthermore, myeloid β‐catenin deletion increased XBP1 messenger RNA splicing, whereas a CRISPR/CRISPR‐associated protein 9‐mediated XBP1 knockout diminished NLRP3/caspase‐1. Conclusion: The myeloid HSF1‐β‐catenin axis controlled NLRP3 activation by modulating the XBP1 signaling pathway. HSF1 activation promoted β‐catenin, which, in turn, inhibited XBP1, leading to NLRP3 inactivation and reduced I/R‐induced liver injury. These findings demonstrated that HSF1/β‐catenin signaling is a novel regulator of innate immunity in liver inflammatory injury and implied the therapeutic potential for management of sterile liver inflammation in transplant recipients. (Hepatology 2016;64:1683‐1698).