# Targeting the NLRP3 inflammasome to limit pathologic sterile inflammation

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $437,500

## Abstract

Project Summary
The NLRP3 inflammasome has been linked to both protective and pathologic immune responses. Its
appropriate activation triggers the innate immune response to invading pathogens including influenza virus,
Staphylococcus aureus and Candida albicans; in contrast aberrant activation of the NLRP3 inflammasome is
implicated in the pathogenesis of a variety of sterile inflammatory diseases. Activation of the NLRP3
inflammasome is a multistep process that culminates in the activation of the cysteine protease caspase-1,
which subsequently results in the processing and secretion of the proinflammatory cytokines IL-1β and IL-18.
The precise steps leading to activation of the NLRP3 inflammasome are not well understood but involve
mitochondrial dysfunction and cation flux. Importantly we have found that the mitochondrial specific lipid
cardiolipin directly binds to NLRP3 and caspase-1 and is required for NLRP3 inflammasome activation. We
propose that the mitochondrion serves as an activating platform for the assembly and activation of the NLRP3
inflammasome. We will define how the mitochondrion specifically interacts with NLRP3 inflammasome
components during the priming and activation steps in NLRP3 inflammasome. We will determine if calcium
flux, the generation of reactive oxygen species, and changes in mitochondrial dynamics trigger the critical
interaction between NLRP3 inflammasome components and the mitochondrion. Numerous sterile inflammatory
processes are caused by inappropriate activation of the NLRP3 inflammasome. We have previously shown the
inflammatory response to acetaminophen-induced hepatotoxicity and pulmonary silicosis is dependent upon
activation of the NLRP3 inflammasome. We will use these two clinically relevant models of NLRP3-dependent
pathogenic sterile inflammation to identify novel therapeutic targets that can disrupt activation of the NLRP3
inflammasome in vivo.

## Key facts

- **NIH application ID:** 9985704
- **Project number:** 5R01AI118719-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Fayyaz S. Sutterwala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985704

## Citation

> US National Institutes of Health, RePORTER application 9985704, Targeting the NLRP3 inflammasome to limit pathologic sterile inflammation (5R01AI118719-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9985704. Licensed CC0.

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