# Innate Immune Regulation by HSF1 in Liver Inflammatory Injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $390,000

## Abstract

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 β-catenin activity leading to
reduced ROS production and NLRP3 activation. Although these results point towards the HSF1-β-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 β-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...

## Key facts

- **NIH application ID:** 10312786
- **Project number:** 5R01AI139552-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Bibo Ke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-01-25 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312786

## Citation

> US National Institutes of Health, RePORTER application 10312786, Innate Immune Regulation by HSF1 in Liver Inflammatory Injury (5R01AI139552-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10312786. Licensed CC0.

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