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


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

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 -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.

© 2021 The Authors.

PMID: 34368651

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