# Disentangling the Death Decision: How Living Cells Release Interleukin-1

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $33,208

## Abstract

Project Abstract
 An immune response begins with the detection of infection by pattern recognition receptors (PRRs).
Notably, some cytosolic PRRs allow for the nucleation and sequential oligomerization of large signaling
complexes called the inflammasome. The inflammasome activates the protease caspase-1. Caspase-1
cleaves pro-form IL-1 family members that exist in a latent state in the cytosol of primed cells. Caspase-1 (and
caspase-11) also cleave the latent cytosolic protein gasdermin D (GSDMD) that when cleaved becomes the
executioner of the inflammatory cell death program termed pyroptosis by incorporation of N terminal fragments
into the inner leaflet of the plasma membrane. GSDMD pore formation is thought to ultimately lead to cellular
lysis. IL-1 family members are unable to be secreted by the conventional protein secretion pathway involving
trafficking through the biosynthetic pathway. Instead, it is thought that inflammasome activation leads to lytic
cell death that allows for the release of cytosolic contents, including cleaved IL-1 family members, into the
extracellular space through large membrane tears.
 A new cell fate that also involves the inflammasome and activation of caspase-1 has been termed
phagocyte hyperactivation. The hyperactive cell fate is characterized by the ability of non-pyroptotic (living)
cells to release cytokines from the conventional biosynthetic pathway while also releasing cytosolic
inflammatory mediators such as IL-1 family members. A major question remains based on our current
understanding of inflammasome signaling and IL-1β release: how can cells with active inflammasomes remain
viable and also release cytosolic IL-1? The goal of this project is to determine how the pyroptotic regulator
GSDMD mediates a non-pyroptotic role in unconventional protein secretion. To accomplish this goal, we aim to
determine if intrinsic differences exist between pyroptotic and hyperactive inflammasomes that differentially
regulate the extent of GSDMD pore formation in lytic (pyroptotic) and non-lytic (hyperactive) contexts. We also
aim to determine the location of cleaved GSDMD fragments after inflammasome signaling and perturbation of
membrane repair to determine the ultimate fate of these GSDMD pores in living cells. Delineation of this novel
mechanism of IL-1 activation and release that does not require cell death may lead to the design of more
efficacious vaccine adjuvants and shift our understanding of the impact of inflammasome signaling on host
immunity and defense against pathogens.

## Key facts

- **NIH application ID:** 9841717
- **Project number:** 5F31AI138369-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Charles Lee Evavold
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,208
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841717

## Citation

> US National Institutes of Health, RePORTER application 9841717, Disentangling the Death Decision: How Living Cells Release Interleukin-1 (5F31AI138369-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841717. Licensed CC0.

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