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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Intercellular transmission of 2',3'-cyclic GMP-AMP (cGAMP) by cGAMP synthase (cGAS) activates bystander cells during host defense.
• The role of this cGAMP transfer in cGAS-dependent autoimmunity is not well understood.

Purpose of the Study:

• To investigate the contribution of intercellular cGAMP transfer to Trex1-associated autoimmunity.
• To determine the downstream signaling events and cellular consequences of cGAMP shuttling in this autoimmune model.

Main Methods:

• Murine bone marrow transplantation model.
• Analysis of NF-κB activation, IRF3 phosphorylation, and interferon signaling.
• Assessment of myeloid cell and lymphocyte survival and accumulation.
• Evaluation of B cell differentiation and T cell priming.
• Induction of skin inflammation via UV light exposure.

Main Results:

• Intercellular cGAMP transfer in Trex1-deficient mice induced NF-κB activation, IRF3 phosphorylation, and interferon signaling in immune cells.
• cGAMP shuttling prevented myeloid cell and lymphocyte death, leading to their accumulation in lymphoid tissues.
• cGAMP transfer did not promote B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming.
• While spontaneous organ disease was not observed, cGAMP-mediated bystander activation triggered interface dermatitis upon UV light exposure, mimicking aspects of cutaneous lupus erythematosus.

Conclusions:

• Intercellular cGAMP transfer propagates cGAS signaling in Trex1-deficient autoimmunity.
• This mechanism contributes to tissue inflammation under specific conditions, such as UV light exposure, highlighting its potential role in autoimmune pathogenesis.