# Targeting Estrogenic pathways in Tregs to promote ARDS resolution

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $816,322

## Abstract

Pneumonia (PNA) is one of the leading causes of death worldwide. PNA can result in devastating acute
inflammatory injury in the lung manifesting in acute respiratory distress syndrome (ARDS). Current treatments for
PNA have focused on the pathogens, but do not target excessive lung inflammation elicited by the host immune
response. Both the emergence of new infections, typified by COVID-19, and the expanding impact of antimicrobial
resistant pathogens, highlight the limitations of our current armamentarium and underscore the need to identify
additional therapeutic targets in PNA-induced ARDS. With the understanding that resolution of PNA is an
actively regulated program to promote return to homeostasis, our work has focused on identifying cellular and
molecular mediators of this resolution phase. Others and we have demonstrated that regulatory T cells (Tregs)
promote resolution of infectious-ARDS.
Our strong preliminary data has identified lung-derived Treg DHX58, which encodes an RNA helicase protein
essential for antiviral responses, as a candidate gene upregulated during the resolution phase of ARDS. DHX58-
deficient animals fail to resolve lung inflammation after Streptococcus pneumoniae-ARDS with significantly
diminished lung Treg numbers during injury resolution, implicating DHX58 in optimal Treg function in vivo. Further,
we observed significantly increased 30-day mortality among carriers of a putative loss-of-function variant of DHX58
with infectious ARDS (71% vs. 47%, p=0.01), underscoring the potential clinical impact of DHX58 in ARDS
outcomes. Our in-silico analysis of the DHX58 promoter identified numerous estrogen responsive elements (ERE).
Indeed, DHX58 expression was induced in Tregs by estradiol (E2). Importantly, our published work showed that
therapeutic E2 promotes resolution of preclinical PNA-ARDS in a Treg-dependent manner. Estrogen receptor beta
(ER) was necessary for both Treg-dependent rescue of lymphopenic hosts and Treg-mediated suppression of
pro-inflammatory cytokine production in macrophages in vitro. Preliminary gene expression analysis and high-
dimensional flow cytometry implicate E2 and its downstream-target, DHX58, in the regulation of critical Treg
transcription factors (TFs), notably Foxp3 and GATA3. Thus, we hypothesize that E2, in part via ER-dependent
upregulation of DHX58, orchestrates critical Treg pro-resolution functions, through regulating expression of key
TFs in Tregs. The goals of this proposal are to determine the cellular, molecular and transcriptional determinants
of E2-ER-DHX58 in Treg-mediated resolution of PNA-ARDS to provide the mechanistic underpinnings of the
regulation and functional role of ER in Tregs.

## Key facts

- **NIH application ID:** 10462918
- **Project number:** 1R01HL163881-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Franco Rafael D'Alessio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $816,322
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462918

## Citation

> US National Institutes of Health, RePORTER application 10462918, Targeting Estrogenic pathways in Tregs to promote ARDS resolution (1R01HL163881-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10462918. Licensed CC0.

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