title: 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.
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 (HSF1M-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 (HSF1FL/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.
  
  
  
  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).
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Shi
authors.initials: S
authors.lastname: Yue
authors.affiliation: Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Changyong
authors.initials: C
authors.lastname: Li
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology & Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Xingliang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ke
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Stem Cell Biology & Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Ying
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.affiliation: Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. xiaqiang@shsmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA. bke@mednet.ucla.edu.
authors.forename: Bibo
authors.initials: B
authors.lastname: Ke
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D058847:Inflammasomes / Q000502:physiology*; D008099:Liver / Q000098:blood supply*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D015427:Reperfusion Injury / Q000209:etiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014157:Transcription Factors; D051176:beta Catenin