Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency
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
Affiliations
Bianca B. Jütte
Department of Medicine III, University Hospital Bonn, Bonn, Germany
Calvin Krollmann
Department of Medicine III, University Hospital Bonn, Bonn, Germany
Kevin Cieslak
Department of Medicine III, University Hospital Bonn, Bonn, Germany
Ruth-Miriam Koerber
Department of Medicine III, University Hospital Bonn, Bonn, Germany
Peter Boor
Institute of Pathology and Division of Nephrology, University Hospital of the RWTH Aachen, Aachen, Germany
Claus M. Graef
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany
Eva Bartok
Department of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; Unit of Experimental Immunology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Mirko Wagner
Department of Chemistry, Ludwig Maximilians University Munich, Munich, Germany
Thomas Carell
Department of Chemistry, Ludwig Maximilians University Munich, Munich, Germany
Jennifer Landsberg
Department of Dermatology, University Hospital Bonn, Bonn, Germany
Pia Aymans
Department of Dermatology, University Hospital Bonn, Bonn, Germany
Jörg Wenzel
Department of Dermatology, University Hospital Bonn, Bonn, Germany
Peter Brossart
Department of Medicine III, University Hospital Bonn, Bonn, Germany
Lino L. Teichmann
Department of Medicine III, University Hospital Bonn, Bonn, Germany; Corresponding author
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.
