# Sterile inflammation and pyroptotic cell death in liver fibrosis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $494,042

## Abstract

Summary
The NLRP3 inflammasome is a multi-protein cytoplasmic complex functioning as a pattern
recognition receptor that has emerged as a key regulator of sterile inflammation and cell death.
Upon activation, NLRP3 assembles a complex comprised of the adaptor protein apoptosis-
associated speck-like protein (ASC) and the serine protease caspase-1. This protease cleaves
and activates inflammasome target cytokines, mainly IL-1β. Caspase 1 activation can also
initiates a distinct form of programmed cell death, called pyroptosis, that allows the release of
active NLRP3 inflammasome particles to the extracellular space
While focused on the investigation of the specific contribution of NLRP3 inflammasome activation
and the downstream mechanisms involved in the development of liver fibrosis, we have made the
following key observations: 1) Persistent global NLRP3 inflammasome activation results in
spontaneous liver fibrosis; 2) Two important consequences of persistent global NLRP3 activation
in the liver include hepatocyte pyroptotic cell death and HSC activation; 3) In murine models and
patients with NASH, caspase 1 activity is increased in circulation; and 4) Blocking IL-1 signaling
during persistent NLRP3 activation rescues mice from inflammatory changes, but not from HSC
activation and fibrosis. These data are remarkable because they identify new molecular pathways
of liver fibrosis and provide a window for discovery of novel therapies. Based on these preliminary
data we propose the CENTRAL HYPOTHESIS that cell- and time-specific NLRP3 inflammasome
activation is a central mechanism that triggers liver fibrogenesis and fibrosis, while pyroptosis and
extracellular inflammasomes are key events leading to amplification and perpetuation of NLRP3
inflammasome activity. To investigate this hypothesis our proposal has following SPECIFIC
AIMS. FIRST we will establish how NLRP3 inflammasome activation modulates HSC phenotype,
fibrogenesis and induces liver fibrosis. SECOND we will determine the role of pyroptosis and
extracellular NRLP3 Inflammasome as a mechanism of amplification and perpetuation of
inflammasome driven fibrogenesis and liver fibrosis. To address these central issues, we have
put together a Multi-PI investigative team including a Pioneered Scientist in Inflammasome
Biology, and Experts in Cell Death, Fibrosis and Liver Pathology. The results of these studies will
uncover crucial aspects of NLRP3 Inflammasome biology and contribution to liver pathology and
may lead to novel therapeutic strategies for treatment of various liver conditions associated with
NLRP3 Inflammasome activation.

## Key facts

- **NIH application ID:** 9957053
- **Project number:** 5R01DK113592-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ariel Feldstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,042
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957053

## Citation

> US National Institutes of Health, RePORTER application 9957053, Sterile inflammation and pyroptotic cell death in liver fibrosis (5R01DK113592-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9957053. Licensed CC0.

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