# Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $196,875

## Abstract

ABSTRACT
IBDs affect 1.3% of U.S. adults. Despite the success of antibody therapies targeting TNFα and IL-23, a
significant fraction of patients does not achieve remission, necessitating the search for novel pathogenic
pathways that can be targeted. The pathogenesis of IBD is dependent on proper regulation of intestinal
immunity. Given their constitutive presence in the intestinal mucosa, group 3 innate lymphoid cells (ILC3)
play a pivotal role in maintaining intestinal homeostasis. ILC3 are vital for defense against extracellular
bacteria through the secretion of IL-17 and IL-22. However, in mouse models of innate immune colitis,
inappropriate activation of ILC3 is a main driver of pathology. Thus, a comprehensive understanding
of ILC3 biology is crucial for potentially targeting their role in IBD. Due to their proximity to the intestinal
lumen, ILC3 make a number of metabolic adaptations to accommodate the surrounding
environment. To systematically characterize these adaptations, we performed untargeted metabolomic
profiling of the major intestinal ILC subsets. In combination with analysis of previously generated RNA-
sequencing data from intestinal ILCs, we identified a significant enrichment of polyamines and
polyamine metabolic enzymes in ILC3. Polyamines are products of arginine metabolism with diverse
functions in cancer, aging, and autoimmunity. Mechanistically, they participate in proliferation,
chromatin accessibility, as well as translation elongation and termination. Preliminary data shows that
dietary polyamines positively regulate the abundance of ILC3. We also found that inhibition of polyamine
synthesis using the drug DFMO impairs IL-22 production by ILC3. Furthermore, administration of
DFMO in vivo has been shown to exacerbate infection by the intestinal pathogen C. rodentium.
Considering these premises, we hypothesize that polyamines positively regulate ILC3 function
and contribute to the immunoregulatory role of ILC3 in colitis. We will interrogate these hypotheses
in the following aims: Aim 1: To evaluate the impact of intracellular polyamines on ILC3 function at
steady state. Synthesis of polyamines is dependent on the rate-limiting enzyme ODC1. We have
generated RorcCreOdc1flox/flox mice, in which polyamine biosynthesis is genetically ablated in all
conventional T cells and ILC3. By studying these mice (Odc1ΔILC3/T), we will selectively interrogate the
importance of polyamines in abundance, functional capacity and proliferation of ILC3. Aim 2: To assess
the contribution of ILC3-intrinsic polyamine metabolism in a model of infectious colitis. We will assess
the function of Odc1-deficient ILC3 during a model of attaching effacing bacterial colitis, the C.
rodentium model, which is highly dependent on ILC3-derived IL-22 for protection. These studies will
further our understanding of the metabolic adaptations of ILC3 as well as the potential role for targeting
these metabolic pathways to treat inflammatory bowel diseases.

## Key facts

- **NIH application ID:** 10528082
- **Project number:** 1R21AI159210-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** MARCO COLONNA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 1
- **Project period:** 2022-05-17 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10528082

## Citation

> US National Institutes of Health, RePORTER application 10528082, Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis (1R21AI159210-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10528082. Licensed CC0.

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