The role of the inflammasome and caspase-1 in trauma and hemorrhage
Caspase-1 is an important enzyme in inflammatory processes with a main function of cleaving pro-forms of inflammatory cytokines IL-1beta and IL-18, which allows them to be released from macrophages and other immune cells. A lot less is known about the role of caspase-1 in non-immune cells such as hepatocytes, the main cell-type in the liver. These cells have been shown to activate caspase-1 but produce little if any IL-1beta or IL-18. Our lab is therefore focusing on identifying the function of caspase-1 activation in non-immune cells during global ischemia-reperfusion and oxidative stress induced by hemorrhagic shock and trauma.
We are also investigating how caspase-1 is activated in non-immune cells in our models. Caspase-1 is activated/cleaved through the activation of a group of proteins that form a platform known as the inflammasome. Multiple types of inflammasome have been described all of which include NOD-like proteins such as NLRP3 and NLRP1. Our lab is working to determine which mechanism of caspase-1 activation is important in end-organs such as the liver during hemorrhagic shock and after trauma. Understanding how the mechanisms behind the immune response to hemorrhage and trauma could identify novel future treatments for these patients and prevent morbidity and mortality from organ failure.
The role of the inflammasome and caspase-1 in sepsis
Proinflammatory cytokines, such as IL-1beta, are known to be extremely important in helping to activate immune responses to fight infection and clear bacteria from the blood and organs. However, too much inflammation can be damaging to cells and tissues, and can lead to organ dysfunction and failure. We are intersted in the role of the inflammasome and caspase-1 in initiating the immune response to surgical infection, and how responses are integrated between immune cells and end organs in order to clear bacteria and resolve infection.
The main model we are using is a model of polymicrobial peritonitis induced by ligating and punturing the cecum to release fecal bacteria into the abdomen. This model of cecal ligation and puncture (CLP) mimics many types of surgical abdominal infection such as a burst appendix or diveticulum and so is relevant to human disease. Understanding how the immune response is regulated by the inflammasome and caspase-1 may provide us with clues about new treatments that may help more effectively treat surgical patients in the future.
Inflammasome activation and metabolic control in the liver and during surgery
The inflammasome and its activation have been strongly implicated in the regulation of many metabolic events, including obesity-induced diabetes and insulin resistance. As the population of the United States as a whole becomes more obese it becomes more important for us to understand how the immune system is affected in these patients and how this affects both elective and emergency surgical outcomes. Our lab is interested in investigating the role of the inflammasome and caspase-1 particularly in the liver of obese subjects, and how the inflammasome affects immune processes that can regulate wound healing, inflammation and infection after hemorrhagic shock and trauma.
Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation. Menzel CL, Sun Q, Loughran PA, Pape HC, Billiar TR, Scott MJ. Mol Med. 2011 17:1031-8. doi: 10.2119/molmed.2011.00015. Epub 2011 Jun 7. PMID: 21666957 | View Publication
Hepatocytes express functional NOD1 and NOD2 receptors: a role for NOD1 in hepatocyte CC and CXC chemokine production. Scott MJ, Chen C, Sun Q, Billiar TR. J Hepatol. 2010 53:693-701. Epub 2010 Jun 16. PMID: 20615568 | View Publication
Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells. Xiang M, Shi X, Li Y, Xu J, Yin L, Xiao G, Scott MJ, Billiar TR, Wilson MA, Fan J. J Immunol. 2011 187:4809-17. Epub 2011 Sep 21. PMID: 21940680 | View Publication