Universität zu Köln

Juette, Bianca B., Krollmann, Calvin, Cieslak, Kevin, Koerber, Ruth-Miriam, Boor, Peter, Graef, Claus M., Bartok, Eva ORCID: 0000-0003-0556-1950, Wagner, Mirko, Carell, Thomas, Landsberg, Jennifer, Aymans, Pia, Wenzel, Jorg, Brossart, Peter and Teichmann, Lino L. (2021). Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency. iScience, 24 (8). CAMBRIDGE: CELL PRESS. ISSN 2589-0042

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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-kappa B 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Juette, Bianca B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krollmann, Calvin UNSPECIFIED UNSPECIFIED UNSPECIFIED Cieslak, Kevin UNSPECIFIED UNSPECIFIED UNSPECIFIED Koerber, Ruth-Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Boor, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Graef, Claus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartok, Eva UNSPECIFIED orcid.org/0000-0003-0556-1950 UNSPECIFIED Wagner, Mirko UNSPECIFIED UNSPECIFIED UNSPECIFIED Carell, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Landsberg, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Aymans, Pia UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenzel, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Brossart, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Teichmann, Lino L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-592805
DOI:	10.1016/j.isci.2021.102833
Journal or Publication Title:	iScience
Volume:	24
Number:	8
Date:	2021
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2589-0042
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GMP-AMP SYNTHASE; BYSTANDER CELLS; MYELOID CELLS; I INTERFERON; RESPONSES; TRIGGERS; SPREADS; DISEASE; DAMAGE; SELF Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59280