# Biology of innate IL-22 during lung fungal infection

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $372,400

## Abstract

Aspergillus fumigatus is an opportunistic mold that causes difficult to treat invasive fungal infections in
immunocompromised and immunosuppressed individuals, often resulting in a lethal outcome. The objective of
this competitive renewal R01 is to build upon our recent work that has uncovered roles for bioactive lipid
mediators in immune responses during lung fungal infection with A. fumigatus. In the previous funding period,
we made three novel findings: (i) IL-33 receptor signaling negatively regulated immunoprotective type 17
responses during A. fumigatus infection, (ii) the eicosanoid PGE2 positively regulated IL-17A and IL-22 induction
and (3) IL-33 receptor signaling negatively regulated PGE2 production (J Immunol 99:2140-2148, 2017). In other
work supported by this proposal, we reported that deficiency in 12/15-lipoxygenase (12/15-LOX, Alox15-/-)
resulted in impaired inflammatory responses and profound susceptibility to lung infection with A. fumigatus (J
Immunol 204:1849-1858, 2020). Intriguingly, a mechanism of susceptibility we observed in Alox15-/- mice was
impaired neutrophil maturation in the bone marrow. Our findings overall have prompted some interesting
questions: (i) how does IL-33 modulate PGE2 during lung fungal infection? (ii) does IL-33 regulate the production
of other bioactive lipids? (iii) can bioactive lipids other than PGE2 modulate immune responses during infection
with A. fumigatus? (iv) are specific bioactive lipids required for or negatively regulate neutrophil maturation during
infection? Lipidomic analysis of lung tissue from A. fumigatus exposed mice demonstrates that IL-33 signaling
is a profound negative regulator of multiple bioactive lipid classes, including prostaglandins,
hydroxydocosahexaenoic acids (HDHAs), hydroxyeicosapentaenoic acids (HEPEs) and
hydroxyeicosatetraenoic acids (HETEs). Data further shows the Alox15-/- mice have a unique lung lipid signature
during A. fumigatus infection, one that may function to modulate neutrophil-mediated immunity to A. fumigatus.
In other studies, employing Il33flox/flox-eGFP reporter mice and a combination of flow cytometry and fluorescent
immunohistochemistry, we show that dendritic cells and neutrophils are immune cell sources of IL-33 whereas
alveolar type II cells are the primary non-immune cell source of IL-33 in the lung during A. fumigatus infection.
Recent studies suggest that the cellular source of IL-33 (i.e. myeloid vs. epithelial) may have a dramatic effect
on the type of immune response. Overall, our hypothesis is that bioactive lipids, regulated by cytokines such as
IL-33 and enzymes such as 12/15/-LOX, tune the inflammatory response during A. fumigatus lung infection. The
specific aims of the proposal are: (1) to determine the mechanism(s) associated with and function of IL-33 and
12/15-LOX-mediated regulation of bioactive lipids during lung fungal infection and (2) to determine how the
cellular source of IL-33 modulates bioactive lipid production and ...

## Key facts

- **NIH application ID:** 10839876
- **Project number:** 5R01HL136211-09
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Chad Steele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,400
- **Award type:** 5
- **Project period:** 2017-01-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839876

## Citation

> US National Institutes of Health, RePORTER application 10839876, Biology of innate IL-22 during lung fungal infection (5R01HL136211-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10839876. Licensed CC0.

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