# Fra-1-A20 Signaling and Resolution of Pneumonia-Induced Sepsis

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $35,178

## Abstract

The counter balancing of pro- and anti-inflammatory gene transcription is crucial for normal
homeostasis after septic tissue injury. Aberrant regulation of this transcriptional balance culminates
in an unchecked systemic inflammation, leading to lung tissue damage and edema, respiratory
failure and ultimately death. However, the exact mechanisms underlying pathological inflammation
in sepsis are poorly understood, and thus the strategies to accelerate the resolution of sepsis are
very limited. Studies in the proposal will test the novel hypothesis that pathogenic signaling
caused by sepsis is the result of a macrophage-specific Fra-1/AP-1 restricted expression of anti-
inflammatory A20, a crucial ubiquitin-editing enzyme that terminates uncontrolled activation of NF-
κB and MAP kinase signaling. Our preliminary studies, using three pre-clinical models of sepsis,
showed that Fra-1 as a crucial mediator of pro-inflammatory responses in sepsis. Endotoxemia
(LPS)- and pseudomonas pneumonia-induced lung injury and inflammation are markedly lower in
Fra-1-deficient mice than wild-type counterparts. Fra-1-deficient mice subjected to injurious dose of
i.t bacterial endotoxin (LPS), showed an accelerated resolution of lung injury compared to wild-type
mice. We found increased expression of Fra-1 largely in alveolar macrophages of cadaveric lungs
infected with E. coli ex vivo and in mice exposed to LPS. Importantly, mice lacking Fra-1 in myeloid
cells survived longer than wild-type mice from septic shock and polymicrobial sepsis. In preliminary
studies, we found reduced levels of LPS-induced NF-κB activation and an increased expression of
A20 in Fra-1-deficient macrophages. A20 haplo-sufficiency in humans and in mice is associated
with heightened levels of systemic inflammation. We will address the specific hypothesis that in the
settings of chronic or pathological sepsis Fra-1 activation secondary to microbial insults restricts
optimal A20 expression and triggers pro-inflammatory response, thereby impairing the resolution of
sepsis. We will use physiological and molecular approaches and tissue-specific knockout mice and
preclinical models of sepsis to test this hypothesis. The specific aims of the proposal are to: 1)
Determine the role and mechanisms of macrophage-specific Fra-1 signaling in mediating
sustained lung injury in pseudomonas pneumonia and sepsis, and 2) Examine the mechanisms by
which Fra-1 restricts A20 transcriptional induction by microbial insults in macrophages, and
determine that Fra-1 restricted A20 signaling is a causative factor of persistent lung injury in
sepsis. The proposed studies will identify novel insights and targets for therapies to accelerate lung
injury repair in patients with pseudomonas pneumonia and sepsis.

## Key facts

- **NIH application ID:** 10140808
- **Project number:** 3R01GM124235-04S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Sekhar P. Reddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $35,178
- **Award type:** 3
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140808

## Citation

> US National Institutes of Health, RePORTER application 10140808, Fra-1-A20 Signaling and Resolution of Pneumonia-Induced Sepsis (3R01GM124235-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140808. Licensed CC0.

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