The long term goals of this project are to determine the role of 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 and, ultimately, in the peripheral blood and skin of patients with 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, here we show that following a single exposure to ultraviolet light (UVB), UVB induces an IFN signature not only in the skin but also in the blood 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 and to what extent UVB-stimulated cGAMP production leads to spreading of the IFN signature in the skin, examine the immune response systemically, and look for cGAMP-dependent tissue injury in both wild type and lupus-prone strains. 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 cGAMP transmission between cells. Since we have detected cGAMP in a subset of patients with systemic lupus erythematosus (SLE), these studies are also highly relevant to human SLE. 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 and cell import pathways that have not previously been studied in the context of autoimmunity. If shown to be important, these pathways could be harnessed therapeutically to abort cGAMP spreading – as will be tested in this proposal. These studies could reverse the paradigm that systemic IFN-I causes the skin IFN signature and also guide more detailed analysis of the cGAS-STING pathway in SLE patients.