| First Author | Jütte BB | Year | 2021 |
| Journal | iScience | Volume | 24 |
| Issue | 8 | Pages | 102833 |
| PubMed ID | 34368651 | Mgi Jnum | J:310084 |
| Mgi Id | MGI:6756272 | Doi | 10.1016/j.isci.2021.102833 |
| Citation | Jutte BB, et al. (2021) Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency. iScience 24(8):102833 |
| abstractText | 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-kappaB 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. |
