# A novel essential inflammasome component propagating inflammatory responses

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $639,524

## Abstract

Inflammasomes are key for the release of the inflammatory cytokines IL-1β, IL-18 and the induction of
pyroptotic cell death. In addition, inflammasomes release polymerized ASC danger particles (pASC), which
perpetuate and propagate inflammasome responses to bystander cells and pASC as well as pASC auto-
antibodies are found in inflammatory disease patient sera. In addition, cytokine release by the non-canonical
inflammasome also requires the canonical NLRP3 inflammasome. However, the mechanisms by which
inflammasomes are controlled are largely elusive. Excessive and uncontrolled NLRP3 and Pyrin
inflammasome activity causes the autoinflammatory diseases Cryopyrinopathies and familial Mediterranean
fever, respectively. Given the important roles of IL-1β and IL-18 in host defense and the pathology of
inflammatory diseases, elucidating the mechanism of inflammasome activation is expected to have a major
impact on the medical field and will be crucial for designing novel and improved treatment options for
inflammatory disease patients.
 Using a proteomics approach, we discovered a novel inflammasome component and identified its role
in mediating a novel and essential step of inflammasome activation, by promoting a distinct ubiquitination of
inflammasome components, reminiscent to other key innate immune pathways. Furthermore, we discovered
that this protein is part of the pASC danger particle released upon inflammasome activation. The research
outlined in this proposal is geared to define the underlying molecular mechanism(s) of this novel activation step
in human macrophages and our novel generated conditional knock-out mice, which are defect in
inflammasome activation and the impact on inflammasome response propagation through pASC danger
particles. We will perform a comprehensive analysis combining biochemical and genetic approaches focusing
on key inflammasomes involved in human disease, namely NLRP3 and Pyrin and the diseases caused by their
uncontrolled inflammasomes, as well as dissecting this activation and propagation mechanism in human
Crypyrinopathy patients.
 We expect that our research will uncover novel molecular mechanisms that change our current
understanding of the pathologies of inflammatory disease and the control mechanisms present in healthy
individuals to prevent inappropriate inflammasome activation. Our studies will therefore be highly significant
and relevant for better understanding disease pathologies and for providing the basis for developing novel
therapies to benefit patients and will therefore positively affect human health.

## Key facts

- **NIH application ID:** 10104431
- **Project number:** 5R01AI134030-03
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Andrea Dorfleutner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $639,524
- **Award type:** 5
- **Project period:** 2019-03-04 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104431

## Citation

> US National Institutes of Health, RePORTER application 10104431, A novel essential inflammasome component propagating inflammatory responses (5R01AI134030-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104431. Licensed CC0.

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