# Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $331,333

## Abstract

PROJECT SUMMARY/ABSTRACT
 Despite major investments, the promise of immunotherapy for Systemic Inflammatory Response
Syndrome (SIRS) remains unfulfilled. A hyperinflammatory SIRS subset suffers much higher mortality, and
thus is in greatest need of new therapies to limit immunopathology. The clinical factors used to define
hyperinflammatory SIRS were inspired by a life-threatening complication of pediatric rheumatic disease called
Macrophage Activation Syndrome (MAS). Recently, MAS was genetically associated with hyperactivity of the
NLRC4 inflammasome and excess Interleukin (IL)-18, strongly suggesting that excess IL-18 is a fundamental
host susceptibility factor for hyperinflammatory SIRS. The objectives of this proposal are to identify the relevant
mechanisms driving IL-18 overproduction and to define the pathways by which IL-18 promotes
hyperinflammation. Our central hypothesis is that intestinal IL-18 overproduction promotes both lymphocyte
hyperactivation and dysfunction to drive hyperinflammation and the MAS phenotype. Our guiding rationale is
that understanding the mechanisms driving hyperinflammatory SIRS will enable rational identification of at-risk
patients, identify potential prevention strategies, and facilitate the use of targeted immunotherapies necessary
to prevent organ dysfunction and death.
 To accomplish our objectives, we first aim to identify the causes of elevated IL-18 in MAS. This will
involve (i) determining the molecular machinery necessary for inflammasome-driven intestinal overproduction
of IL-18; (ii) isolating the specific microbial factors affecting intestinal IL-18 production and testing their effects
on experimental MAS; (iii) determining the cellular sources (intestinal vs. myeloid) of inducible IL-18 in models
of systemic hyperinflammation; and (iv) correlating systemic IL-18 levels with fecal colonization in children with
Systemic Juvenile Idiopathic Arthritis, who are at high risk for MAS. Our second aim is to define the
mechanisms by which IL-18 promotes hyperinflammation. This will involve (i) determining the immunologic
mechanisms by which IL-18 promotes models of hyperinflammation; (ii) determining how cytotoxic impairment
and excess IL-18 synergistically promote immunopathology; and (iii) determining how NLRC4 hyperactivity and
excess IL-18 promote susceptibility to infection.
 These experiments will contribute significantly to defining new genetic and mechanistic drivers of
hyperinflammation, and they will guide precision diagnostics, prevention strategies, and targeted treatments to
prevent morbidity and mortality in hyperinflammatory SIRS. The proposed research is innovative because it
originates with mechanisms derived from monogenic human hyperinflammatory diseases to understand and
manipulate SIRS physiology more broadly. Ultimately, we expect completion of the proposed studies to provide
specific insights useful for guiding early detection of the hyperinflammatory SIRS phenotype and novel means
t...

## Key facts

- **NIH application ID:** 10377827
- **Project number:** 7R01HD098428-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Scott William Canna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,333
- **Award type:** 7
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377827

## Citation

> US National Institutes of Health, RePORTER application 10377827, Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation (7R01HD098428-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10377827. Licensed CC0.

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