Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency. Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency

Intercellular transmission of the second messenger 2′,3′‐cGAMP, synthesized by the viral DNA sensor cGAMP synthase (cGAS), is a potent mode of bystander activation during host defense. However, whether this mechanism also contributes to cGAS-dependent autoimmunity remains unknown. Here, using a murine bone marrow transplantation strategy, we demonstrate that, in Trex1-/--associated autoimmunity, cGAMP shuttling from radioresistant to immune cells induces NF-κB activation, interferon regulatory protein 3 (IRF3) phosphorylation and subsequent interferon signaling. cGAMP travel prevented myeloid cell and lymphocyte death, promoting their accumulation in secondary lymphoid tissue. Nonetheless, it did not stimulate B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming in the steady state. Although cGAMP-mediated bystander activation did not induce spontaneous organ disease, it did trigger interface dermatitis after UV light exposure, similar to cutaneous lupus erythematosus. These findings reveal that, in Trex1-deficiency, intercellular cGAMP transfer propagates cGAS signaling and, under conducive conditions, causes tissue inflammation. Overall design: Total RNA was isolated from single-cell suspensions of bone marrow from Cgas-/- mice and Trex1-/-;Sting1gt/gt mice (called dKO). In addition, total RNA was isolated from single-cell suspensions of spleens from dKO mice 12 weeks after they were lethally irradiated and transplanted with Cgas-/- or dKO bone marrow. 3'-mRNA Seq was performed on an Illumina HiSeq 2500.