# Dissecting interplay between electrophilic stress and IkBz-driven inflammation

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

## Abstract

Abstract
Electrophilic stress is a broad phenomenon caused by compounds that are reactive to thiol groups (-SH), such
as cysteine residues within cellular proteins. We found that electrophilic stress response induced by dimethyl
itaconate (DI), a derivative of the metabolite itaconate, mediates a strong, yet very selective inhibitory effect on
the immune activation. In macrophages, DI treatment downregulates production of a subset of cytokines such as
IL-6 or IL-12 but does not affect other cytokines such as TNF. We found that this selective effect occurs through
inhibition of IκBζ, a transcription factor of the NF-κB family, which is commonly induced during immune activation.
IκBζ selectively regulates inflammation in several important contexts: (1) in macrophages, IκBζ regulates the
secondary transcriptional response to toll-like receptor stimulation and its deficiency leads to defective production
of a subset of cytokines such as IL-6 and IL-12, but not TNF; (2) in epithelial cells, IκBζ is a primary regulator of
the transcriptional response to IL-17; (3) in T-cells, it is an indispensable transcription factor facilitating Th17
polarization. Importantly, medical and population genetics studies have identified NFΚBIZ (the gene encoding
IκBζ) as a major susceptibility locus for psoriasis, an IL-17-associated autoimmune condition. We have
demonstrated that in vivo administration of DI completely ameliorates development of pathology in a mouse model
of psoriasis. Therefore, a deeper understanding of the connection between IκBζ and electrophilic stress has the
strong potential to uncover novel therapeutic avenues for treatment of autoimmune conditions, such as psoriasis.
Moreover, although the major studied cellular response to electrophilic stress is the Keap1/Nrf2 pathway, we
show that the effect of DI on IκBζ is independent of Nrf2. Our preliminary data suggest the existence of a
discrete Nrf2-independent molecular pathway starting at Keap1 engagement by electrophiles and
culminating in selective inhibition of IκBζ translation. Defining the mechanistic details of this pathway will
deepen the general understanding of immune regulation and will provide novel therapeutic strategies in
autoimmune diseases driven by the IκBζ-IL-17 axis. We aim to uncover key members and mechanisms of
this pathway using the following converging strategies: 1) define the mechanism of IκBζ inhibition by
electrophilic stress at the level of Keap1 and 2) define the mechanism of translational regulation of Nfkbiz
mRNA in conditions of electrophilic stress. Completion of the proposed Aims will lay the foundation for future
detailed in vitro and in vivo studies of the novel regulator/regulators of the IκBζ activation program. Ultimately, we
aim to study the role of the novel IκBζ regulators identified by this proposal in the context of an inflammatory
condition such as psoriasis, which will be the subject of a future R01 application.

## Key facts

- **NIH application ID:** 10452024
- **Project number:** 1R21AI163980-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Monika Bambouskova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $196,875
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452024

## Citation

> US National Institutes of Health, RePORTER application 10452024, Dissecting interplay between electrophilic stress and IkBz-driven inflammation (1R21AI163980-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10452024. Licensed CC0.

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