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Updated: Jun 12, 2026
Ex Situ Normothermic Machine Perfusion of Donor Livers
Published on: May 26, 2015
Reduced pannexin 1-IL-33 axis function in donor livers increases risk of MRSA infection in liver transplant
Hao Li1, Xiaoyu Yu2, Baojie Shi3,4
1Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Abstract:
Liver transplantation patients are at increased risk for methicillin-resistant Staphylococcus aureus (MRSA) infection, but the molecular mechanism remains unclear. We found that genetic predisposition to low pannexin 1 (PANX1) expression in donor livers was associated with MRSA infection in human liver transplantation recipients. Using Panx1 and Il-33-knockout mice for liver transplantation models with MRSA tail vein injection, we demonstrated that Panx1 deficiency increased MRSA-induced liver injury and animal death. We found that decreased PANX1 expression in the liver led to reduced release of adenosine triphosphate (ATP) from hepatocytes, which further reduced the activation of P2X2, an ATP-activating P2X receptor. Reduced P2X2 function further decreased the NLRP3-mediated release of interleukin-33 (IL-33), reducing hepatic recruitment of macrophages and neutrophils. Administration of mouse IL-33 to Panx1 mice significantly (P = 0.011) ameliorated MRSA infection and animal death. Reduced human hepatic IL-33 protein abundance also associated with increased predisposition to MRSA infection. Our findings reveal that genetic predisposition to reduced PANX1 function increases risk for MRSA infection after liver transplantation by decreasing hepatic host innate immune defense, which can be attenuated by IL-33 treatment.
Insights
Genetic predisposition to low pannexin 1 (PANX1) expression in donor livers increases MRSA infection risk in liver transplant patients. Restoring interleukin-33 (IL-33) levels can mitigate this risk.
Area of Science:
- Immunology
- Transplantation Surgery
- Infectious Diseases
Background:
- Liver transplant recipients face heightened risk of methicillin-resistant Staphylococcus aureus (MRSA) infections.
- The underlying molecular mechanisms contributing to this increased susceptibility are not fully understood.
Purpose of the Study:
- To investigate the role of pannexin 1 (PANX1) expression in donor livers and its association with MRSA infection post-liver transplantation.
- To elucidate the molecular pathway linking PANX1 deficiency to increased MRSA susceptibility and explore potential therapeutic interventions.
Main Methods:
- Utilized Panx1 and Il-33 knockout mouse models for liver transplantation.
- Administered MRSA via tail vein injection to assess infection severity and outcomes.
- Measured adenosine triphosphate (ATP) release, P2X2 receptor activation, and NLRP3-mediated interleukin-33 (IL-33) release.
- Assessed hepatic recruitment of macrophages and neutrophils.
Main Results:
- Panx1 deficiency in donor livers exacerbated MRSA-induced liver injury and mortality in mouse models.
- Reduced PANX1 expression led to decreased hepatocyte ATP release, impaired P2X2 activation, and diminished IL-33 release.
- Lower IL-33 levels resulted in reduced recruitment of immune cells (macrophages, neutrophils) to the liver.
- IL-33 administration significantly improved outcomes in Panx1-deficient mice during MRSA infection.
- Reduced human hepatic IL-33 abundance correlated with increased MRSA infection risk.
Conclusions:
- Genetic predisposition to low PANX1 expression in donor livers compromises innate immune defense against MRSA in liver transplant recipients.
- The pathway involves reduced ATP release, impaired P2X2 signaling, and decreased IL-33 production, leading to inadequate immune cell infiltration.
- IL-33 treatment represents a potential therapeutic strategy to enhance host defense and mitigate MRSA infection risk in this patient population.
