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

Bianca B. Juette, Calvin Krollmann, Kevin Cieslak, Ruth-Miriam Koerber, Peter Boor, Claus M. Graef, Eva Bartok, Mirko Wagner, Thomas Carell, Jennifer Landsberg, Pia Aymans, Jorg Wenzel, Peter Brossart, Lino L. Teichmann

Research output: Contribution to journalA1: Web of Science-article

Abstract

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.

Original languageEnglish
Article number102833
JournalIscience
Volume24
Issue number8
Number of pages21
DOIs
Publication statusPublished - 2021

Keywords

  • GMP-AMP SYNTHASE
  • BYSTANDER CELLS
  • MYELOID CELLS
  • I INTERFERON
  • RESPONSES
  • TRIGGERS
  • SPREADS
  • DISEASE
  • DAMAGE
  • SELF

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