# Radioresistant Innate Immunity in SAVI Tissue-Specific Autoinflammation

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $209,375

## Abstract

The cGas/STING cytosolic DNA sensing pathway detects microbial DNA and plays a critical role in host defense.
Growing evidence indicates that self-DNA that accumulates in the cytosol also engages cGAS to incite
inflammation. In addition, a series of gain-of-function mutations that result in constitutive activation of STING
have now been associated with a debilitating auto-inflammatory disease known as SAVI (STING-Associated-
Vasculopathy with onset in Infancy). These patients suffer from severe vasculitic lesions and progressive
interstitial lung disease (ILD), and frequently succumb to treatment-resistant ILD-associated with fibrosis. Similar
to the lung disorders associated with other inflammatory or fibrotic lung diseases, very little is known about the
pathogenic mechanisms in these patients. Thus, a better understanding of the mechanisms responsible for these
conditions is needed in order to develop more effective therapies. We have recently developed a murine model
for the most common SAVI mutation, STINGV154M (VM), and shown that these mice recapitulate the human
disease by a variety of criteria, including the development of inflammatory/fibrotic lung disease. These VM mice
provide a unique experimental tool for exploring the cell types and molecular mechanisms responsible for the
initiation and progression of fibrotic lung disease. Rag1-deficiency completely rescues VM mice from both lung
inflammation and lung fibrosis pointing to a critical role of the adaptive immunity in VM ILD. The role of STING
has been focused on myeloid cells and VM mice have an expanded and activated myeloid/neutrophil
compartment. However, radiation chimera studies have identified a key role for radioresistant cells in lung fibrosis
as lethally irradiated VM mice reconstituted with WT bone marrow stem cells develop extremely severe lung
disease even though these chimeras completely lack any VM-derived hematopoietic cells. Preliminary data
implicate lymphatic endothelial cells (LECs) as initiators of BALT formation in VM mice. The goal of this
application is to further explore the radioresistant innate immune cells that are directly or indirectly activated by
the VM mutation and define the mechanisms by which these cells promote lung inflammation. Our approach will
involve: (1) the in vivo analysis of a novel VM conditional KI line crossed to endothelial-restricted Cre deleter
strains and other relevant controls, (2) scRNAseq comparison of stromal populations including lymphatic and
vascular endothelial cells isolated from WT and VM mice; and (3) analysis of endothelial cells from VM and WT
mice following in vitro activation by the VM mutation or more conventional STING agonists. There is an urgent
need to identify better therapies for patients afflicted with autoimmune and autoinflammatory lung disorders and
the studies proposed in this application should provide critical insights that will enable us to design the most
relevant therapeutic targets. Further, these...

## Key facts

- **NIH application ID:** 10899703
- **Project number:** 5R21AI178978-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Katherine A. Fitzgerald
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2023-08-04 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899703

## Citation

> US National Institutes of Health, RePORTER application 10899703, Radioresistant Innate Immunity in SAVI Tissue-Specific Autoinflammation (5R21AI178978-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899703. Licensed CC0.

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