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 muri...

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Published in:iScience 2021-08, Vol.24 (8), p.102833-102833, Article 102833
Main Authors: 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, Teichmann, Lino L.
Format: Article
Language:English
Subjects:
Cell biology
Immune response
Immunity
Immunology
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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. [Display omitted] •In Trex1−/−-associated autoimmunity radioresistant cells transfer cGAMP to immune cells•cGAMP shuttling induces NF-κB activation, IRF3 and IFN signaling in vivo•Intercellular cGAMP transmission is sufficient to cause UV skin inflammation Immunology; Immunity; Immune response; Cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2021.102833