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

• Main Authors: Bianca B. Jütte, Calvin Krollmann, Kevin Cieslak, Ruth-Miriam Koerber, Peter Boor, Claus M. Graef, Eva Bartok, Mirko Wagner, Thomas Carell, Jennifer Landsberg, Pia Aymans, Jörg Wenzel, Peter Brossart, Lino L. Teichmann
• Format: Article
• Language: English
• Published: Elsevier 2021-08-01
• Series: iScience
• Subjects: Immunology; Immunity; Immune response; Cell biology
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004221008014

Summary: 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 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.