Thursday, March 30, 2023
3/30/2023
PROJECT SUMMARY Liver ischemia and reperfusion injury (IRI), an innate immunity-dominant local sterile inflammatory response, is a major cause for hepatic dysfunction and failure following liver transplantation, resection, and hemorrhagic shock. Oxidative stress has been recognized as an important factor in the pathogenesis of hepatic IRI, in which IR activates liver macrophages (Kupffer cells) to generate reactive oxygen species (ROS), leading to sterile inflammation in the liver. ROS is an endogenous `danger' signal and can be released from necrotic or stressed cells to trigger NLRP3 inflammasome activation. Recent study revealed that activation of the NLRP3 inflammasome required ROS-dependent NEK7, a serine-threonine kinase involved in mitotic cell division. NEK7 directly binds to NLRP3 and promotes inflammatory response, suggesting that NEK7 is an essential mediator to trigger innate immunity during inflammatory response. It has been shown that activation of antioxidant defense system prevents ROS-induced liver damage whereas disruption of NLRP3 adaptor protein ASC reduces inflammatory response in liver IRI. Moreover, mice with myeloid-specific HSF1 knockout (HSF1M- KO) enhanced NLRP3 functions and exacerbated IR-induced liver damage through activation of transcription factor X-box-binding protein (XBP1). Ultimately, HSF1 activation increased ß-catenin activity leading to reduced ROS production and NLRP3 activation. Although these results point towards the HSF1-ß-catenin axis as a novel master-switch of innate immunity in liver inflammatory injury, it remains unknown how HSF1 modulates NEK7 function leading to reduced NLRP3 activation in response to IR-induced stress. The TLR4/TRAF6 axis mediates the NOX2-dependent production of ROS, which is crucial for the activation of TXNIP. TLR signaling can interact with transforming growth factor ß-activated kinase 1 (TAK1) to initiate inflammatory cascade whereas activation of NEK7 promotes NLRP3 inflammasome pathway. Thus, TXNIP and TAK1 are likely to be essential for the HSF1-mediated regulation of NEK7 functions during liver inflammatory injury. The overall goal of this proposal is to dissect the functions and molecular mechanisms of HSF1-dependent regulation of NEK7 function in IR-stressed livers. The hypothesis is that HSF1 regulates NEK7-mediated innate immune responses in hepatic IRI by: 1) controlling TAK1 activity; and 2) inhibiting TXNIP activation. To test this hypothesis, the following specific aims are proposed: i) dissect mechanisms by which HSF1 controls the TAK1-NEK7 interaction in IR-stressed liver; and ii) determine mechanisms by which HSF1 regulates the TXNIP-NEK7 axis in IR-stressed liver. These studies will increase the understanding of the hepatic regulatory network of innate immunity in IR-induced liver inflammation. These findings will also have far reaching implications for therapeutic modulation of ischemic tissue damage in organ transplantation and other sterile inflammatory disease states.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
