# cGAMP as an immunotransmitter of the interferon response to UV light

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2021 · $427,130

## Abstract

Project Summary
 The long-term goals of this project are to determine the role of the cGAS-STING pathway and the
messenger cyclic dinucleotide cGAMP, as a local and systemic immunotransmitter of the IFN response
following skin exposure to UVB light. In addition, we seek to determine the significance of these observations
in a relevant mouse model of SLE.
 SLE patients characteristically have a type I interferon (IFN-I) signature in peripheral blood cells and this
same signature is prominent in lesional and non-lesional skin. While it is generally assumed that systemic
immune activation leads to dissemination of the IFN-I response to tissues, we observed that, following a single
exposure to ultraviolet light (UVB), UVB induces an IFN signature not only in the skin but also in the blood and
kidneys of wild type mice. Since we observed that IFN-I produced soon after UV exposure requires the DNA
activated cytoplasmic sensor cGAS, we hypothesize that cGAMP, the cyclic dinucleotide synthetic product of
cGAS, is itself an immunotransmitter that is responsible for spreading the IFN-I response locally and systemically.
In this proposal, we explore how UVB stimulated cGAMP production leads to spreading of the IFN signature in
the skin, examine the effects on local immune response in the draining lymph nodes, and look for cGAMP
dependent tissue inflammation in both wild type and lupus-prone strains. To achieve these Aims, we take
advantage of genetically modified mice that are deficient in cGAS or ENPP1 (ectonucleotide pyrophosphatase
phosphodiesterase-1 that hydrolyzes cGAMP after export from cells) and utilize reagents that can be exploited
to manipulate the cGAS-STING pathway. We specifically interrogate the cGAMP transporters: connexins,
SLC19A1 and the Volume Regulated Anion Channel (VRAC) LRRC8, to determine which transporters control
cGAMP spreading and under what conditions.
 The significance of these studies are that they will help define the genetic and molecular mechanisms
responsible for UVB induction of IFN-I, define how the signal spreads and, possibly, indicate how lupus flares
occur following exposure to UVB. In addition, the research focuses on an enzyme, ENPP1, that has not
previously been studied in the context of autoimmunity and, if shown to be important, could be harnessed
therapeutically to abort cGAMP spreading. These studies could reverse the paradigm that systemic IFN-I causes
the skin IFN signature. Since we have detected cGAMP in blood of a subset of patients with systemic lupus
erythematosus (SLE), the results of these studies will have strong translational significance.

## Key facts

- **NIH application ID:** 10215860
- **Project number:** 1R21AR077842-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Keith B. Elkon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,130
- **Award type:** 1
- **Project period:** 2021-09-23 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215860

## Citation

> US National Institutes of Health, RePORTER application 10215860, cGAMP as an immunotransmitter of the interferon response to UV light (1R21AR077842-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10215860. Licensed CC0.

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