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Jütte, Bianca B.; Krollmann, Calvin; Cieslak, Kevin; Koerber, Ruth-Miriam; Boor, Peter; Graef, Claus M.; Bartok, Eva; Wagner, Mirko; Carell, Thomas; Landsberg, Jennifer; Aymans, Pia; Wenzel, Jörg; Brossart, Peter and Teichmann, Lino L. (2021): Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency. In: Iscience, Vol. 24, No. 8, 102833

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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-kappa B activation, interferon regulatory factor 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. 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.

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